Indazole, benzisoxazole, and benzisothiazole kinase inhibitors

ABSTRACT

Compounds having the formula 
                         
are useful for inhibiting protein tyrosine kinases. The present invention also discloses methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

This application is a continuation of U.S. patent application No.11/867,887 filed Oct. 5, 2007, which is a divisional of U.S. patentapplication No. 10/842,292, filed May 22, 2004, now U.S. Pat. No.7,297,709, which claims priority to U.S. patent application No.60/472,810, filed May 22, 2003, each of which is herein incorporated byreference.

TECHNICAL FIELD

The present invention relates to compounds which are useful forinhibiting protein tyrosine kinases, methods of making the compounds,compositions containing the compounds, and methods of treatment usingthe compounds.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases (PTKs) are enzymes which catalyse thephosphorylation of specific tyrosine residues in cellular proteins. Thispost-translational modification of these substrate proteins, oftenenzymes themselves, acts as a molecular switch regulating cellproliferation, activation, or differentiation. Aberrant or excessive PTKactivity has been observed in many disease states including benign andmalignant proliferative disorders as well as diseases resulting frominappropriate activation of the immune system (e.g., autoimmunedisorders), allograft rejection, and graft vs. host disease. Inaddition, endothelial-cell specific receptor PTKs such as KDR and Tie-2mediate the angiogenic process, and are thus involved in supporting theprogression of cancers and other diseases involving inappropriatevascularization (e.g., diabetic retinopathy, choroidalneovascularization due to age-related macular degeneration, psoriasis,arthritis, retinopathy of prematurity, and infantile hemangiomas).

The identification of effective small compounds which specificallyinhibit signal transduction and cellular proliferation by modulating theactivity of tyrosine kinases to regulate and modulate abnormal orinappropriate cell proliferation, differentiation, or metabolism istherefore desirable. In particular, the identification of methods andcompounds that specifically inhibit the function of a tyrosine kinasewhich is essential for antiogenic processes or the formation of vascularhyperpermeability leading to edema, ascites, effusions, exudates, andmacromolecular extravasation and matrix deposition as well as associateddisorders would be beneficial.

SUMMARY OF THE INVENTION

In its principle embodiment the present invention provides a compound offormula (I)

or a therapeutically acceptable salt thereof, wherein

A is selected from the group consisting of indolyl, phenyl, pyrazinyl,pyridazinyl, pyridinyl, pyrimidinyl, and thienyl;

X is selected from the group consisting of O, S, and NR⁹;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl,aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl,heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,(NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkenyl, (NR^(a)R^(b))alkyl,(NR^(a)R^(b))alkynyl, (NR^(a)R^(b))carbonylalkenyl, and(NR^(a)R^(b))carbonylalkyl;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl,hydroxy, and LR⁶; provided that at least two of R³, R⁴, and R⁵ are otherthan LR⁶;

L is selected from the group consisting of(CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n) and CH₂C(O)NR⁷, wherein m and n areindependently 0 or 1, and wherein each group is drawn with its left endattached to A;

R⁶ is selected from the group consisting of hydrogen, aryl, cycloalkyl,heterocyclyl, and 1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can beoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy,arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy,haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), and (NR^(c)R^(d))alkyl;

R⁷ and R⁸ are independently selected from the group consisting ofhydrogen and alkyl;

R⁹ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,hydroxyalkyl, and (NR^(a)R^(b))alkyl;

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl,arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl,heterocyclylalkyl, and heterocyclylsulfonyl; and

R^(c) and R^(d) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.

In another embodiment the present invention provides a compound offormula (II)

or a therapeutically acceptable salt thereof, wherein

X is selected from the group consisting of O, S, and NR⁹;

R¹ and R² are independently selected from the group consisting ofhydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy,aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl,heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl,heterocyclyloxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,(NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkenyl, (NR^(a)R^(b))alkyl,(NR^(a)R^(b))carbonylalkenyl, and (NR^(a)R^(b))carbonylalkyl;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy;

L is selected from the group consisting of(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n) and CH₂C(O)NR⁷, wherein m and n areindependently 0 or 1, and wherein each group is drawn with its left endattached to the ring substituted with R³ and R⁴;

R⁷ and R⁵ are independently selected from the group consisting ofhydrogen and alkyl;

R⁹ is selected from the group consisting of hydrogen, alkenyl,alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,hydroxyalkyl, and (NR^(a)R^(b))alkyl;

R¹⁰ and R¹¹ are independently selected from the group consisting ofhydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy,arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, and —NR^(c)R^(d);

R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; and

R^(c) and R^(d) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein X is O and A, R¹, R², R³, R⁴, and R⁵ are as definedin formula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and R^(c)R^(d))alkyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); and m, n, R^(c), R^(d), R¹, R², R³,R⁴R⁷, and R⁸ are as defined in formula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and (NR^(c)R^(d))alkyl; L is(CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;R³, R⁴, R⁷, and R⁵ are hydrogen; and R^(c) and R^(d) are selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl; L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); m and n are 0;R¹ and R² are independently selected from the group consisting ofhydrogen and alkoxy; and R³, R⁴, R⁷, and R⁵ are hydrogen.

In another embodiment, the present invention provides a compound offormula (I) wherein X is S and A, R¹, R², R³, R⁴, and R⁵ are as definedin formula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and (NR^(c)R^(d))alkyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); and m, n, R^(c), R^(d), R², R³, R⁴,R⁷, and R⁸ are as defined in formula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and (NR^(c)R^(d))alkyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;R³, R⁴, R⁷, and R⁸ are hydrogen; and R^(c) and R^(d) are selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl; L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); m and n are 0;R¹ and R² are independently selected from the group consisting ofhydrogen and alkoxy; and R³, R⁴, R⁷, and R⁸ are hydrogen.

In another embodiment, the present invention provides a compound offormula (I) wherein X is NR⁹; and A, R¹, R², R³, R⁴, R⁵, and R⁹ are asdefined in formula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and R^(c)R^(d))alkyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); and m, n, R^(c), R^(d), R¹, R², R³,R⁷, R⁸, and R⁹ are as defined in formula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo,haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and R^(c)R^(d))alkyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;R³, R⁴, R⁷, and R⁸ are hydrogen; R⁹ is selected from the groupconsisting of hydrogen and alkyl; and R^(c) and R^(d) are selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is1,3-benzodioxolyl; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0;R¹ and R² are independently selected from the group consisting ofhydrogen and alkoxy; R³, R⁴, R⁷, and R⁸ are hydrogen; and R⁹ is selectedfrom the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is cycloalkyloptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R^(c), R^(d), R¹, R², R³, R⁴R⁷, and R⁸ are as defined in formula(I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is cycloalkylwherein the cycloalkyl is selected from the group consisting ofcyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); mand n are 0; R¹ and R² are independently selected from the groupconsisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy,(NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonylalkenyl; R³ and R⁴ are independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo,haloalkoxy, and hydroxy; R⁷ and R⁸ are hydrogen; R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl;and R^(c) and R^(d) are independently selected from the group consistingof hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is cycloalkylwherein the cycloalkyl is cyclopentyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;and R³, R⁴, R⁷, and R⁵ are hydrogen.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is cycloalkyloptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R^(c), R^(d), R¹, R², R³, R⁴, R⁷, and R⁸ are as defined in formula(I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is cycloalkylwherein the cycloalkyl is selected from the group consisting ofcyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹ and R² are independently selected from the groupconsisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy,(NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonylalkenyl; R³ and R⁴ are independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo,haloalkoxy, and hydroxy; R⁷ and R⁸ are hydrogen; R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl;and R^(c) and R^(d) are independently selected from the group consistingof hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is cycloalkylwherein the cycloalkyl is cyclopentyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;and R³, R⁴, R⁷, and R⁸ are hydrogen.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is cycloalkyloptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d)(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R^(c), R^(d), R¹, R², R³, R⁴, R⁷, R⁸, and R⁹ are as defined informula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is cycloalkylwherein the cycloalkyl is selected from the group consisting ofcyclobutyl, cyclopentyl, and cyclohexyl, wherein the cycloalkyl isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹ and R² are independently selected from the groupconsisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, hydroxy,(NR^(a)R^(b))alkoxy, (R^(a)R^(b))alkyl, and(NR^(a)R^(b))carbonylalkenyl; R³ and R⁴ are independently selected fromthe group consisting of hydrogen, alkyl, alkoxy, alkoxyalkoxy, halo,haloalkoxy, and hydroxy; R⁷ and R⁸ are hydrogen; R⁹ is selected from thegroup consisting of hydrogen and alkyl; R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl;and R^(c) and R^(d) are independently selected from the group consistingof hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is cycloalkylwherein the cycloalkyl is cyclopentyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;R³, R⁴, R⁷, and R⁸ are hydrogen; and R⁹ is selected from the groupconsisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is heterocyclyloptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(R^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R^(c), R^(d), R¹, R², R³, R⁴, R⁷, and R⁸ are as defined in formula(I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is heterocyclylwherein the heterocyclyl is selected from the group consisting of furyl,isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl,wherein the heterocyclyl is optionally substituted with one, two, orthree substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,—NR^(c)R^(d), (R^(c)R^(d))alkyl, and oxo; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkoxy, alkyl, halo, hydroxy, (NR^(a)R^(b))alkoxy,(NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonylalkenyl; R³ and R⁴ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R⁷ and R⁸ arehydrogen; R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen and alkyl; and R^(c) and R^(d) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is O; R⁵ is LR⁶; R⁶ is heterocyclylwherein the heterocyclyl is thienyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;and R³, R⁴, R⁷, and R⁸ are hydrogen.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is heterocyclyloptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R^(c), R^(d), R¹, R², R³, R⁴R⁷, and R⁸ are as defined in formula(I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is heterocyclylwherein the heterocyclyl is selected from the group consisting of furyl,isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl,wherein the heterocyclyl is optionally substituted with one, two, orthree substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,—NR^(c)R^(d), (NR^(c)R^(d))alkyl, and oxo; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkoxy, alkyl, halo, hydroxy, (NR^(a)R^(b))alkoxy,(NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonylalkenyl; R³ and R⁴ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R⁷ and R⁸ arehydrogen; R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen and alkyl; and R^(c) and R^(d) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is S; R⁵ is LR⁶; R⁶ is heterocyclylwherein the heterocyclyl is thienyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;and R³, R⁴, R⁷, and R⁸ are hydrogen.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is heterocyclyloptionally substituted with one, two, or three substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R^(c), R^(d), R¹, R², R³, R⁴, R⁷, R⁸, and R⁹ are as defined informula (I).

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is heterocyclylwherein the heterocyclyl is selected from the group consisting of furyl,isoxazolyl, isothiazolyl, oxazolyl, pyridinyl, thiazolyl, and thienyl,wherein the heterocyclyl is optionally substituted with one, two, orthree substituents independently selected from the group consisting ofalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl,—NR^(c)R^(d), (NR^(c)R^(d))alkyl, and oxo; L is(CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkoxy, alkyl, halo, hydroxy, (NR^(a)R^(b))alkoxy,(NR^(a)R^(b))alkyl, and (NR^(a)R^(b))carbonylalkenyl; R³ and R⁴ areindependently selected from the group consisting of hydrogen, alkyl,alkoxy, alkoxyalkoxy, halo, haloalkoxy, and hydroxy; R⁷ and R⁸ arehydrogen; R⁹ is selected from the group consisting of hydrogen andalkyl; R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen and alkyl; and R^(c) and R^(d) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (I) wherein A is phenyl; X is NR⁹; R⁵ is LR⁶; R⁶ is heterocyclylwherein the heterocyclyl is thienyl; L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); m and n are 0; R¹ and R² areindependently selected from the group consisting of hydrogen and alkoxy;R³, R⁴, R⁷, and R⁸ are hydrogen; and R⁹ is selected from the groupconsisting of hydrogen and alkyl.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I), or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method forinhibiting protein kinase in a patient in recognized need of suchtreatment comprising administering to the patient a therapeuticallyacceptable amount of a compound of formula (I), or a therapeuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method fortreating cancer in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of formula (I), or a therapeutically acceptablesalt thereof.

In another embodiment, the present invention provides a compound offormula (II) wherein L is CH₂C(O)NR⁷; and X, R¹, R², R³, R⁴, R⁷, R¹⁰,and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is CH₂C(O)NR⁷; and R¹, R², R³, R⁴, R⁷,R⁹, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is CH₂C(O)NR⁷; and R¹, R², R³, R⁴, R⁷,R⁹, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is CH₂C(O)NR⁷; R¹, R², R³, R⁴, and R⁷are hydrogen; R⁹ is selected from the group consisting of hydrogen andalkyl; R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is CH₂C(O)NR⁷; R¹, R², R³, R⁴, and R⁷are hydrogen; R⁹ is selected from the group consisting of hydrogen andalkyl; R¹⁰ and R¹¹ independently selected from the group consisting ofhydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), andaryloxy wherein the aryloxy is phenoxy; and R^(c) and R^(d) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is CH₂C(O)NR⁷; R¹, R², R³, R⁴, and R⁷are hydrogen; R⁹ is selected from the group consisting of hydrogen andalkyl; R¹⁰ and R¹¹ independently selected from the group consisting ofhydrogen, alkyl, halo, and haloalkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); and m, n, X,R¹, R², R³, R⁴, R⁷, R⁸, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; and L, R¹, R², R³, R⁴, R⁹, R¹⁰, and R¹¹are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁵)(CH₂)_(n);and m, n, R¹, R², R³, R⁴, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are as defined informula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is selected from the groupconsisting of alkoxyalkyl, alkyl, alkylcarbonyl, aryl,heterocyclylalkyl, hydroxyalkyl, and (NR^(a)R^(b))alkyl; and R^(a),R^(b), R¹, R², R³, R⁴, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; and R¹, R², R³, R⁴,R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁵ are hydrogen; R⁹ is hydrogen; one of R¹ and R² isselected from the group consisting of hydrogen and halo and the other isselected from the group consisting of hydroxy, hydroxyalkyl, and(NR^(a)R^(b))alkyl; and R^(a), R^(b), R³, R⁴, R¹⁰, and R¹¹ are asdefined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² isselected from the group consisting of hydrogen and halo and the other isselected from the group consisting of hydroxy, hydroxyalkyl, and(NR^(a)R^(b))alkyl; one of R³ and R⁴ is hydrogen and the other isselected from the group consisting of alkoxyalkoxy, alkyl, halo,haloalkoxy, and hydroxy; R¹⁰ and R¹¹ are independently selected from thegroup consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, and —NR^(c)R^(d); R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl;and R^(c) and R^(d) are independently selected from the group consistingof hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁷, R⁸, and R⁹ are hydrogen; R⁴ is selectedfrom the group consisting of hydrogen and halo; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR^(c)R^(d); and R^(c) and R^(d) are independently selected from thegroup consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁷, R⁸, and R⁹ are hydrogen; R⁴ is selectedfrom the group consisting of hydrogen and halo; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein thearyloxy is phenoxy; and R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁷, R⁸, and R⁹ are hydrogen; R⁴ is selectedfrom the group consisting of hydrogen and halo; and R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkyl,halo, and haloalkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁷, and R⁸ are hydrogen; R⁹ is alkyl; R⁴ isselected from the group consisting of hydrogen and halo; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR^(c)R^(d); and R^(c) and R^(d) are independently selected from thegroup consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁷, and R⁸ are hydrogen; R⁹ is alkyl; R⁴ isselected from the group consisting of hydrogen and halo; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein thearyloxy is phenoxy; and R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁷, and R⁸ are hydrogen; R⁹ is alkyl; R⁴ isselected from the group consisting of hydrogen and halo; and R¹⁰ and R¹¹are independently selected from the group consisting of hydrogen, alkyl,halo, and haloalkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is halo; and R³, R⁴, R¹⁰, and R¹¹ are as definedin formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is halo; R³ and R⁴ are independently selectedfrom the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo,haloalkoxy, and hydroxy; R¹⁰ and R¹¹ are selected from the groupconsisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d),and aryloxy wherein the aryloxy is phenoxy; and R^(c) and R^(d) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹, L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n), mand n are 0, R⁷ and R⁸ are hydrogen, R⁹ is hydrogen, one of R¹ and R² ishydrogen and the other is heterocyclylalkoxy; and R³, R⁴, R¹⁰, and R¹¹are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹, L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n), mand n are 0, R⁷ and R⁵ are hydrogen, R⁹ is hydrogen, one of R¹ and R² ishydrogen and the other is heterocyclylalkoxy; R³ and R⁴ areindependently selected from the group consisting of hydrogen,alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R¹⁰ and R¹¹ areselected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl,alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein the aryloxy isphenoxy; and R^(c) and R^(d) are independently selected from the groupconsisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹, L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n), mand n are 0, R⁷ and R⁸ are hydrogen, R⁹ is hydrogen, one of R¹ and R² ishydrogen and the other is heterocyclylalkoxy wherein the heterocyclyl isselected from the group consisting of morpholinyl, piperidinyl,pyridinyl, pyrrolyl, pyrrolidinyl optionally substituted with oxo, and3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl; R³ and R⁴ are independentlyselected from the group consisting of hydrogen, alkoxyalkoxy, alkyl,halo, haloalkoxy, and hydroxy; R¹⁰ and R¹¹ are selected from the groupconsisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d),and aryloxy wherein the aryloxy is phenoxy; and R^(c) and R^(d) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting of(NR^(a)R^(b))carbonylalkenyl and (NR^(a)R^(b))alkoxy; and R^(a), R^(b),R³, R⁴, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁵ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting of(NR^(a)R^(b))carbonylalkenyl and (NR^(a)R^(b))alkoxy; R³ and R⁴ areindependently selected from the group consisting of hydrogen,alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R¹⁰ and R¹¹ areselected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl,alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein the aryloxy isphenoxy; R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen, alkyl, alkylsulfonyl, arylsulfonyl,haloalkylsulfonyl, and heterocyclylsulfonyl; and R^(c) and R^(d) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting of(NR^(a)R^(b))carbonylalkenyl and (NR^(a)R^(b))alkoxy; R³ and R⁴ areindependently selected from the group consisting of hydrogen,alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R¹⁰ and R¹¹ areselected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl,alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein the aryloxy isphenoxy; R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen, alkyl, alkylsulfonyl, arylsulfonyl wherein thearyl is phenyl, haloalkylsulfonyl, and heterocyclylsulfonyl wherein theheterocyclyl is thienyl; and R^(c) and R^(d) are independently selectedfrom the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁵ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting ofaryloxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclyloxyalkyl;and R³, R⁴, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting ofaryloxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclyloxyalkyl;R³ and R⁴ are independently selected from the group consisting ofhydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R¹⁰ andR¹¹ are selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein thearyloxy is phenoxy; and R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is aryloxyalkyl wherein the aryl is phenyloptionally substituted with halo; R³ and R⁴ are independently selectedfrom the group consisting of hydrogen, alkoxyalkoxy, alkyl, halo,haloalkoxy, and hydroxy; R¹⁰ and R¹¹ are selected from the groupconsisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d),and aryloxy wherein the aryloxy is phenoxy; and R^(c) and R^(d) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is heterocyclyl wherein the heterocyclyl isselected from the group consisting of pyridinyl and thienyl; R³ and R⁴are independently selected from the group consisting of hydrogen,alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R¹⁰ and R¹¹ areselected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl,alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein the aryloxy isphenoxy; and R^(c) and R^(d) are independently selected from the groupconsisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is heterocyclylalkyl wherein the heterocyclyl isselected from the group consisting of morpholinyl and piperazinylwherein the piperazinyl is optionally substituted with alkyl; R³ and R⁴are independently selected from the group consisting of hydrogen,alkoxyalkoxy, alkyl, halo, haloalkoxy, and hydroxy; R¹⁰ and R¹¹ areselected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl,alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxy wherein the aryloxy isphenoxy; and R^(c) and R^(d) are independently selected from the groupconsisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is heterocyclyloxyalkyl wherein the heterocyclylis pyridinyl; R³ and R⁴ are independently selected from the groupconsisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, andhydroxy; R¹⁰ and R¹¹ are selected from the group consisting of hydrogen,alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxywherein the aryloxy is phenoxy; and R^(c) and R^(d) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting of alkoxy,alkoxyalkoxy, and alkyl; and R³, R⁴, R¹⁰, and R¹¹ are as defined informula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; one of R¹ and R² ishydrogen and the other is selected from the group consisting of alkoxy,alkoxyalkoxy, and alkyl; R³ and R⁴ are independently selected from thegroup consisting of hydrogen, alkoxyalkoxy, alkyl, halo, haloalkoxy, andhydroxy; R¹⁰ and R¹¹ are selected from the group consisting of hydrogen,alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), and aryloxywherein the aryloxy is phenoxy; and R^(c) and R^(d) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; R¹ and R² arehydrogen; and R³, R⁴, R¹⁰, and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; R¹ and R² arehydrogen; one of R³ and R⁴ is hydrogen and the other is selected fromthe group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, andhydroxy; and R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; R¹ and R² arehydrogen; one of R³ and R⁴ is hydrogen and the other is selected fromthe group consisting of alkoxyalkoxy, alkyl, halo, haloalkoxy, andhydroxy; and R¹⁰ and R¹¹ are selected from the group consisting ofhydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(c)R^(d), andaryloxy wherein the aryloxy is phenoxy; and R^(c) and R^(d) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; R¹ and R² arehydrogen; R³ and R⁴ are hydrogen; and R¹⁰ and R¹¹ are as defined informula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; R¹ and R² arehydrogen; R³ and R⁴ are hydrogen; and R¹⁰ and R¹¹ are selected from thegroup consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy,cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,—NR^(c)R^(d), and aryloxy wherein the aryloxy is phenoxy; and R^(c) andR^(d) are independently selected from the group consisting of hydrogenand alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is NR⁹; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R⁷ and R⁸ are hydrogen; R⁹ is hydrogen; R¹ and R² arehydrogen; R³ and R⁴ are alkyl; and R¹⁰ and R¹¹ are selected from thegroup consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy,cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro,—NR^(c)R^(d), and aryloxy wherein the aryloxy is phenoxy; and R^(c) andR^(d) are independently selected from the group consisting of hydrogenand alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein R¹ and R² are independently selected from the groupconsisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy,aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy,hydroxyalkyl, (NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkenyl,(NR^(a)R^(b))alkyl, (NR^(a)R^(b))carbonylalkenyl, and(NR^(a)R^(b))carbonylalkyl; and X, L, R^(a), R^(b), R³, R⁴, R¹⁰, and R¹¹are as defined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is O and L, R¹, R², R³, R⁴, R¹⁰, and R¹¹ are asdefined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is O; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R¹, R², R³, R⁴, R⁷, R⁸, R¹⁰, and R¹¹ are as defined in formula(II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is O; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR^(a)R^(b); and R^(a) and R^(b) are independently selected from thegroup consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is O; L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), and aryloxy wherein thearyloxy is phenoxy; and R^(a) and R^(b) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is O; L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); mand n are 0; R¹ is heterocyclylalkoxy; R², R³, R⁴, R⁷, and R⁸ arehydrogen; R¹⁰ and R¹¹ are independently selected from the groupconsisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, and —NR^(a)R^(b); and R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is O; L is (CH₂)_(m)N(R⁷)C(O)N(R³)(CH₂)_(n); mand n are 0; R¹ is heterocyclylalkoxy wherein the heterocyclyl ismorpholinyl; R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), and aryloxy wherein thearyloxy is phenoxy; and R^(a) and R^(b) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is O; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹ is selected from the group consisting of alkoxy, alkyl,halo, and haloalkoxy; R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹are independently selected from the group consisting of hydrogen,alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), and aryloxywherein the aryloxy is phenoxy; and R^(a) and R^(b) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is S and L, R¹, R², R³, R⁴, R¹⁰, and R¹¹ are asdefined in formula (II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); andm, n, R¹, R², R³, R⁴, R⁷, R⁸, R¹⁰, and R¹¹ are as defined in formula(II).

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano,halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and—NR^(a)R^(b); and R^(a) and R^(b) are independently selected from thegroup consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), and aryloxy wherein thearyloxy is phenoxy; and R^(a) and R^(b) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹, R², R³, R⁴, R⁷, and R⁸ are hydrogen; and R¹⁰ and R¹¹are independently selected from the group consisting of hydrogen, alkyl,halo, and haloalkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹ is heterocyclylalkoxy; R², R³, R⁴, R⁷, and R⁸ arehydrogen; R¹⁰ and R¹¹ are independently selected from the groupconsisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl,aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, and —NR^(a)R^(b); and R^(a) and R^(b) areindependently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹ is heterocyclylalkoxy wherein the heterocyclyl ismorpholinyl; R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹ areindependently selected from the group consisting of hydrogen, alkoxy,alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), and aryloxy wherein thearyloxy is phenoxy; and R^(a) and R^(b) are independently selected fromthe group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound offormula (II) wherein X is S; L is (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n); mand n are 0; R¹ is selected from the group consisting of alkoxy, alkyl,halo, and haloalkoxy; R², R³, R⁴, R⁷, and R⁸ are hydrogen; R¹⁰ and R¹¹are independently selected from the group consisting of hydrogen,alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy,haloalkyl, hydroxy, hydroxyalkyl, nitro, —NR^(a)R^(b), and aryloxywherein the aryloxy is phenoxy; and R^(a) and R^(b) are independentlyselected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (II), or a therapeuticallyacceptable salt thereof, in combination with a therapeuticallyacceptable carrier.

In another embodiment, the present invention provides a method forinhibiting protein kinase in a patient in recognized need of suchtreatment comprising administering to the patient a therapeuticallyacceptable amount of a compound of formula (II), or a therapeuticallyacceptable salt thereof.

In another embodiment, the present invention provides a method fortreating cancer in a patient in recognized need of such treatmentcomprising administering to the patient a therapeutically acceptableamount of a compound of formula (II), or a therapeutically acceptablesalt thereof.

DETAILED DESCRIPTION OF THE INVENTION

All publications, issued patents, and patent applications cited hereinare hereby incorporated by reference.

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

As used in the present specification the following terms have themeanings indicated:

The term “alkenyl,” as used herein, refers to a straight or branchedchain group of one to six carbon atoms containing at least onecarbon-carbon double bond.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxyalkoxy,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through another alkoxy group.

The term “alkoxyalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one alkoxy group.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon of one to six carbonatoms. Preferred alkyl groups of the present invention are of one tothree carbon atoms. Most preferred alkyl groups are methyl and ethyl.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.

The term “alkylsulfonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicor tricyclic fused ring system wherein one or more of the fused rings isa phenyl group. Bicyclic fused ring systems are exemplified by a phenylgroup fused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Tricyclic fused ring systems are exemplified by a bicyclic fused ringsystem fused to a monocyclic cycloalkenyl group, as defined herein, amonocyclic cycloalkyl group, as defined herein, or another phenyl group.Aryl groups include, but are not limited to, anthracenyl, azulenyl,fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.The aryl groups of the present invention can be optionally substitutedwith one, two, three, four, or five substituents independently selectedfrom the group consisting of alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy,arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy,haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl,nitro, —NR^(c)R^(d), (R^(c)R^(d))alkyl, and oxo; wherein the second arylgroup, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy,the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl canbe further optionally substituted with one, two, three, four, or fivegroups independently selected from the group consisting of alkenyl,alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkyl, nitro, and oxo.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one aryl group.

The term “arylcarbonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a carbonyl group.

The term “arylalkoxy,” as used herein, refers to an aryl group attachedto the parent molecular moiety through an alkoxy group.

The term “aryloxy,” as used herein, refers to an aryl group attached tothe parent molecular moiety through an oxygen atom.

The term “aryloxyalkyl,” as used herein, refers to an aryloxy groupattached to the parent molecular moiety through an alkyl group.

The term “arylsulfonyl,” as used herein, refers to an aryl groupattached to the parent molecular moiety through a sulfonyl group.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “carboxy,” as used herein, refers to —CO₂H.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkenyl,” as used herein, refers to a non-aromatic cyclicor bicyclic ring system having three to ten carbon atoms and one tothree rings, wherein each five-membered ring has one double bond, eachsix-membered ring has one or two double bonds, each seven- andeight-membered ring has one to three double bonds, and each nine- toten-membered ring has one to four double bonds. Examples of cycloalkenylgroups include, but are not limited to, cyclohexenyl,octahydronaphthalenyl, and norbornylenyl.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,bicyclic, or tricyclic hydrocarbon ring system having three to twelvecarbon atoms. Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[3.1.1]heptyl, andadamantyl.

The cycloalkyl groups of the present invention can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, —NR^(c)R^(d),(NR^(c)R^(d))alkyl, and oxo.

The terms “halo,” and “halogen,” as used herein, refer to F, Cl, Br, andI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “haloalkylsulfonyl,” as used herein, refers to a haloalkylgroup attached to the parent molecular moiety through a sulfonyl group.

The term “heterocyclyl,” as used herein, represents a monocyclic,bicyclic, or tricyclic ring system wherein one or more rings is a four-,five-, six-, or seven-membered ring containing one, two, or threeheteroatoms independently selected from the group consisting ofnitrogen, oxygen, and sulfur. Monocyclic ring systems are exemplified byany 3- or 4-membered ring containing a heteroatom independently selectedfrom the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or7-membered ring containing one, two or three heteroatoms wherein theheteroatoms are independently selected from the group consisting ofnitrogen, oxygen and sulfur. The 3- and 4-membered rings have no doublebonds, the 5-membered ring has from 0-2 double bonds and the 6- and7-membered rings have from 0-3 double bonds. Representative examples ofmonocyclic ring systems include, but are not limited to, azetidine,azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan,imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline,isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine,oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline,oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole,pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole,thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholinesulfone, thiopyran, triazine, triazole, and trithiane. Bicyclic ringsystems are exemplified by any of the above monocyclic ring systemsfused to phenyl ring, a monocyclic cycloalkyl group as defined herein, amonocyclic cycloalkenyl group, as defined herein, or another monocyclicheterocyclyl ring system. Representative examples of bicyclic ringsystems include but are not limited to, benzimidazole, benzothiazole,benzothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran,benzodioxine, 1,3-benzodioxole, cinnoline, dihydrobenzimidazole,indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran,isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine,pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline,tetrahydroisoquinoline, tetrahydroquinoline, and thiopyranopyridine.Tricyclic rings systems are exemplified by any of the above bicyclicring systems fused to a phenyl ring, a monocyclic cycloalkyl group asdefined herein, a monocyclic cycloalkenyl group as defined herein, oranother monocyclic heterocyclyl ring system. Representative examples oftricyclic ring systems include, but are not limited to, acridine,carbazole, carboline, dibenzofuran, dibenzothiophene, naphthofuran,naphthothiophene, oxanthrene, phenazine, phenoxathiin, phenoxazine,phenothiazine, thianthrene, thioxanthene, and xanthene. Heterocyclylgroups can be attached to the parent molecular moiety through a carbonatom or a nitrogen atom in the group.

The heterocyclyl groups of the present invention can be optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy,arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy,haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy,hydroxyalkyl, nitro, —NR^(c)R^(d), (NR^(c)R^(d))alkyl, and oxo; whereinthe aryl, the aryl part of the arylalkoxy, the arylalkyl, and thearyloxy, the second heterocyclyl group, and the heterocyclyl part of theheterocyclylalkyl can be further optionally substituted with one, two,three, four, or five groups independently selected from the groupconsisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.

The term “heterocyclylalkenyl,” as used herein, refers to an alkenylgroup substituted with at least one heterocyclyl group.

The term “heterocyclylalkoxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an alkoxy group.

The term “heterocyclylalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one heterocyclyl group.

The term “heterocyclyloxy,” as used herein, refers to a heterocyclylgroup attached to the parent molecular moiety through an oxygen atom.

The term “heterocyclyloxyalkyl,” as used herein, refers to an alkylgroup substituted with at least one heterocyclyloxy group.

The term “heterocyclylsulfonyl,” as used herein, refers to aheterocyclyl group attached to the parent molecular moiety through asulfonyl group.

The term “hydroxy,” as used herein, refers to —OH.

The term “hydroxyalkoxy,” as used herein, refers to a hydroxy groupattached to the parent molecular moiety through an alkoxy group.

The term “hydroxyalkyl,” as used herein, refers to an alkyl groupsubstituted with at least one hydroxy group.

The term “nitro,” as used herein, refers to —NO₂.

The term “—NR^(a)R^(b),” as used herein, represents two groups, R^(a)and R^(b), which are attached to the parent molecular moiety through anitrogen atom. R^(a) and R^(b) are independently selected from the groupconsisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl,aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl,wherein the aryl, the aryl part of the arylalkyl and the arylcarbonyl,the heterocyclyl, the heterocyclyl part of the heterocyclylalkyl and theheterocyclylsulfonyl can be further optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl,haloalkoxy, nitro, and oxo.

The term “(NR^(a)R^(b))alkenyl,” as used herein, represents an alkenylgroup substituted with at least one —NR^(a)R^(b) group.

The term “(NR^(a)R^(b))alkoxy,” as used herein, represents an—NR^(a)R^(b) group attached to the parent molecular moiety through analkoxy group.

The term “(NR^(a)R^(b))alkyl,” as used herein, represents an alkyl groupsubstituted with at least one —NR^(a)R^(b) group.

The term “(NR^(a)R^(b))alkynyl,” as used herein, represents an alkynylgroup substituted with at least one —NR^(a)R^(b) group.

The term “(NR^(a)R^(b))carbonyl,” as used herein, represents an(NR^(a)R^(b)) group attached to the parent molecular moiety through acarbonyl group.

The term “(NR^(a)R^(b))carbonylalkenyl,” as used herein, represents analkenyl group substituted with at least one (R^(a)R^(b))carbonyl group.

The term “(NR^(a)R^(b))carbonylalkyl,” as used herein, represents analkyl group substituted with at least one (R^(a)R^(b))carbonyl group.

The term “—NR^(c)R^(d),” as used herein, represents two groups, R^(c)and R^(d), which are attached to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are independently selected from the groupconsisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl,wherein the aryl, the aryl part of the arylalkyl, the heterocyclyl, andthe heterocyclyl part of the heterocyclylalkyl can be further optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of alkenyl, alkoxy,alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.

The term “(NR^(c)R^(d))alkyl,” as used herein, represents an alkyl groupsubstituted with at least one —NR^(c)R^(d) group.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂.

The compounds of the present invention can exist as therapeuticallyacceptable salts. The term “therapeutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent invention which are water or oil-soluble or dispersible, whichare suitable for treatment of diseases without undue toxicity,irritation, and allergic response; which are commensurate with areasonable benefit/risk ratio, and which are effective for theirintended use. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting an —NR^(a)R^(b)group with a suitable acid. Representative acid addition salts includeacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate, lactate, maleate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Also, —NR^(a)R^(b) groups in thecompounds of the present invention can be quaternized with methyl,ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl,diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, andsteryl chlorides, bromides, and iodides; and benzyl and phenethylbromides. Examples of acids which can be employed to formtherapeutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

The present compounds can also exist as therapeutically acceptableprodrugs. The term “therapeutically acceptable prodrug,” refers to thoseprodrugs or zwitterions which are suitable for use in contact with thetissues of patients without undue toxicity, irritation, and allergicresponse, are commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use. The term “prodrug,” refers tocompounds which are rapidly transformed in vivo to parent compounds offormula (I) or (II) for example, by hydrolysis in blood.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I) or (II), as well as therapeuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcomposition. Accordingly, the invention further provides pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of formula (I) or (II), or therapeutically acceptable saltsthereof, and one or more pharmaceutically acceptable carriers, diluents,or excipients. The compounds of formula (I) and (II) and therapeuticallyacceptable salts thereof are as described above. The carrier(s),diluent(s), or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of formula(I) or (II), or a therapeutically acceptable salt thereof, with one ormore pharmaceutically acceptable carriers, diluents, or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of formula (I) or(II), depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight, and condition of the patient, orpharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of an active ingredient per dose.Preferred unit dosage formulations are those containing a daily dose orsub-dose, as herein above recited, or an appropriate fraction thereof,of an active ingredient. Furthermore, such pharmaceutical formulationsmay be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous, or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s). In addition, compounds of the present invention can beadministered using conventional drug delivery technology, for example,intra-arterial stents.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by cumminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like.Lubricants used in these dosage forms include sodium oleate, sodiumchloride, and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, betonite, xanthan gum, and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitable comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelating, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/orand absorption agent such as betonite, kaolin, or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage, or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of formula (I) and (II), and therapeutically acceptablesalts thereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphophatidylcholines.

The compounds of formula (I) and (II), and therapeutically acceptablesalts thereof, may also be delivered by the use of monoclonal antibodiesas individual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of formula (I) or (II) for the treatment of neoplastic growth,for example colon or breast carcinoma, will generally be in the range of0.1 to 100 mg/kg body weight of recipient (mammal) per day and moreusually in the range of 1 to 10 mg/kg body weight per day.

The compounds of the present invention and therapeutically acceptablesalts thereof, may be employed alone or in combination with othertherapeutic agents for the treatment of the above-mentioned conditions.In particular, in anti-cancer therapy, combination with otherchemotherapeutic, hormonal, or antibody agents is envisaged as well ascombination with surgical therapy and radiotherapy. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of formula (I) or (II), or atherapeutically acceptable salt thereof, and the use of at least oneother cancer treatment method. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one other pharmaceutically active agent, preferably ananti-neoplastic agent. The compound(s) of formula (I) or (II) and theother pharmaceutically active agent(s) may be administered together orseparately and when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) or (II) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

The compounds of formula (I) or (II), or therapeutically acceptablesalts thereof, and at least one additional cancer treatment therapy maybe employed in combination concomitantly or sequentially in anytherapeutically appropriate combination with such other anti-cancertherapies. In one embodiment, the other anti-cancer therapy is at leastone additional chemotherapeutic therapy including administration of atleast one anti-neoplastic agent. The administration in combination of acompound of formula (I) or (II), or therapeutically acceptable saltsthereof, with other anti-neoplastic agents may be in combination inaccordance with the invention by administration concomitantly in (1) aunitary pharmaceutical composition including both compounds or (2)separate pharmaceutical compositions each including one of thecompounds. Alternatively, the combination may be administered separatelyin a sequential manner wherein one anti-neoplastic agent is administeredfirst and the other second or vice versa. Such sequential administrationmay be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in acell-cycle specific manner, i.e., are phase specific and act at aspecific phase of the cell cycle, or bind DNA and act in a noncell-cycle specific manner, i.e., are non-cell cycle specific andoperate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds andsalts of formula (I) or (II) include the following:

(1) cell cycle specific anti-neoplastic agents including, but notlimited to, diterpenoids such as paclitaxel and its analog docetaxel;vinca alkaloids such as vinblastine, vincristine, vindesine, andvinorelbine; epipodophyllotoxins such as etoposide and teniposide;fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine;antimetabolites such as allopurinol, fludurabine, methotrexate,cladrabine, cytarabine, mercaptopurine, and thioguanine; andcamptothecins such as 9-amino camptothecin, irinotecan, topotecan,CPT-11, and the various optical forms of7-(-4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;

(2) cytotoxic chemotherapeutic agents including, but not limited to,alkylating agents such as melphalan, chlorambucil, cyclophosphamide,mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine,and dacarbazine; anti-tumor antibiotics such as doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dacttainomycin, and mithramycin;and platinum coordination complexes such as cisplatin, carboplatin, andoxaliplatin; and

(3) other chemotherapeutic agents including, but not limited to,anti-estrogens such as tomixefen, toremifene, raloxifene, droloxifene,and iodoxyfene; progesterogens such as megastrol acetate; aromataseinhibitors such as anastrozole, letrazole, vorazole, and exemestane;antiandrogens such as flutamide, nilutamide, bicalutamide, andcyproterone acetate; LHRH agonists and antagonists such as goserelinacetate and luprolide, testosterone 5α-dihydroreductase inhibitors suchas finasteride; metallopreteinase inhibitors such as marimastat;antiprogestogens; urokinase plasminogen activator receptor functioninhibitors; growth factor function inhibitors such as inhibitors of thefunctions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growthfactor receptor (EGFR), platelet derived growth factor receptor (PDGFR),vascular endothelial growth factor receptor (VEGFR and TIE-2 (other thanthose VEGFR and TIE-2 inhibitors described in the present invention));and other tyrosine kinase inhibitors such as inhibitors of CDK2 and CDK4inhibitors.

Determination of Biological Activity

The in vitro potency of compounds in inhibiting these protein kinasesmay be determined by the procedures detailed below.

The potency of compounds can be determined by the amount of inhibitionof the phosphorylation of an exogenous substrate (e.g., syntheticpeptide (Z. Songyang et al., Nature. 373:536-539) by a test compoundrelative to control.

KDR Tyrosine Kinase Production Using Baculovirus System:

The coding sequence for the human KDR intra-cellular domain (aa789-1354)was generated through PCR using cDNAs isolated from HUVEC cells. Apoly-His6 sequence was introduced at the N-terminus of this protein aswell. This fragment was cloned into transfection vector pVL1393 at theXba 1 and Not 1 site. Recombinant baculovirus (BV) was generated throughco-transfection using the BaculoGold Transfection reagent (PharMingen).Recombinant BV was plaque purified and verified through Westernanalysis. For protein production, SF-9 cells were grown in SF-900-IImedium at 2×106/ml, and were infected at 0.5 plaque forming units percell (MOI). Cells were harvested at 48 hours post infection.

Purification of KDR

SF-9 cells expressing (His)₆ KDR (aa789-1354) were lysed by adding 50 mlof Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10%glycerol, 1% Triton X-100, 1 mM PMSF, 10 μg/ml aprotinin, 1 μg/mlleupeptin) to the cell pellet from 1 L of cell culture. The lysate wascentrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4° C.The cell lysate was applied to a 5 ml NiCl₂ chelating sepharose column,equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCl. KDR was eluted usingthe same buffer containing 0.25 M imidazole. Column fractions wereanalyzed using SDS-PAGE and an ELISA assay (below) which measures kinaseactivity. The purified KDR was exchanged into 25 mM HEPES, pH7.5, 25 mMNaCl, 5 mM DTT buffer and stored at −80° C.

Compounds of the present invention inhibited KDR at IC₅₀'s between about0.003 μM and about 40 μM. Preferred compounds inhibited KDR at IC₅₀'sbetween about 0.003 μM and about 0.1 μM.

Human Tie-2 Kinase Production and Purification

The coding sequence for the human Tie-2 intra-cellular domain(aa775-1124) was generated through PCR using cDNAs isolated from humanplacenta as a template. A poly-His₆ sequence was introduced at theN-terminus and this construct was cloned into transfection vector pVL1939 at the Xba 1 and Not 1 site. Recombinant BV was generated throughco-transfection using the BaculoGold Transfection reagent (PharMingen).Recombinant BV was plaque purified and verified through Westernanalysis. For protein production, SF-9 insect cells were grown inSF-900-II medium at 2×106/ml, and were infected at MOI of 0.5.Purification of the His-tagged kinase used in screening was analogous tothat described for KDR.

Human Flt-1 Tyrosine Kinase Production and Purification

The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles,Calif.) was used. A nucleotide sequence encoding poly-His6 was placed 5′to the nucleotide region encoding the entire intracellular kinase domainof human Flt-1 (amino acids 786-1338). The nucleotide sequence encodingthe kinase domain was generated through PCR using cDNA librariesisolated from HUVEC cells. The histidine residues enabled affinitypurification of the protein as a manner analogous to that for KDR andZAP70. SF-9 insect cells were infected at a 0.5 multiplicity andharvested 48 hours post infection.

EGFR Tyrosine Kinase Source

EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 μL) and theEGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat# PF011-100).

Expression of ZAP70

The baculoviral expression vector used was pVL1393. (Pharmingen, LosAngeles, Calif.) The nucleotide sequence encoding amino acids M(H)₆LVPR₉S was placed 5′ to the region encoding the entirety of ZAP70 (aminoacids 1-619). The nucleotide sequence encoding the ZAP70 coding regionwas generated through PCR using cDNA libraries isolated from Jurkatimmortalized T-cells. The histidine residues enabled affinitypurification of the protein (vide infra). The LVPR₉S bridge constitutesa recognition sequence for proteolytic cleavage by thrombin, enablingremoval of the affinity tag from the enzyme. SF-9 insect cells wereinfected at a multiplicity of infection of 0.5 and harvested 48 hourspost infection.

Extraction and Purification of ZAP70

SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 μg/ml leupeptin, 10μg/ml aprotinin and 1 mM sodium orthovanadate. The soluble lysate wasapplied to a chelating sepharose HiTrap column (Pharmacia) equilibratedin 50 mM HEPES, pH 7.5, 0.3 M NaCl. Fusion protein was eluted with 250mM imidazole. The enzyme was stored in buffer containing 50 mM HEPES, pH7.5, 50 mM NaCl and 5 mM DTT.

Protein Kinase Source

Lck, Fyn, Src, Blk, Csk, and Lyn, and truncated forms thereof may becommercially obtained (e.g., from Upstate Biotechnology Inc. (SaranacLake, N.Y.) and Santa Cruz Biotechnology Inc. (Santa Cruz, Calif.)) orpurified from known natural or recombinant sources using conventionalmethods.

Enzyme Linked Immunosorbent Assay (ELISA) for PTKs

Enzyme linked immunosorbent assays (ELISA) were used to detect andmeasure the presence of tyrosine kinase activity. The ELISA wereconducted according to known protocols which are described in, forexample, Voller, et al., 1980, “Enzyme-Linked Immunosorbent Assay,” In:Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp359-371 Am. Soc. of Microbiology, Washington, D.C.

The disclosed protocol was adapted for determining activity with respectto a specific PTK. For example, preferred protocols for conducting theELISA experiments is provided below. Adaptation of these protocols fordetermining a compound's activity for other members of the receptor PTKfamily, as well as non-receptor tyrosine kinases, are well within theabilities of those in the art. For purposes of determining inhibitorselectivity, a universal PTK substrate (e.g., random copolymer ofpoly(Glu4 Tyr), 20,000-50,000 MW) was employed together with ATP(typically 5 μM) at concentrations approximately twice the apparent Kmin the assay.

The following procedure was used to assay the inhibitory effect ofcompounds of this invention on KDR, Flt-1, Flt-4, Tie-1, Tie-2, EGFR,FGFR, PDGFR, IGF-1-R, c-Met, Lck, hck, Blk, Csk, Src, Lyn, fgr, Fyn andZAP70 tyrosine kinase activity:

Buffers and Solutions:

-   PGTPoly (Glu,Tyr) 4:1-   Store powder at −20° C. Dissolve powder in phosphate buffered saline    (PBS) for 50 mg/ml solution. Store 1 ml aliquots at −20° C. When    making plates dilute to 250 μg/ml in Gibco PBS.    Reaction Buffer: 100 mM Hepes, 20 mM MgCl₂, 4 mM MnCl₂, 5 mM DTT,    0.02% BSA, 200 μM NaVO₄, pH 7.10-   ATP: Store aliquots of 100 mM at −20° C. Dilute to 20 μM in water-   Washing Buffer: PBS with 0.1% Tween 20-   Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in PBS-   TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just    before use or use K-Blue Substrate from Neogen-   Stop Solution: 1M Phosphoric Acid-   Procedure    1. Plate Preparation:

Dilute PGT stock (50 mg/ml, frozen) in PBS to a 250 μg/ml. Add 125 μlper well of Corning modified flat bottom high affinity ELISA plates(Corning #25805-96). Add 125 μl PBS to blank wells. Cover with sealingtape and incubate overnight 37° C. Wash 1× with 250 μl washing bufferand dry for about 2 hrs in 37° C. dry incubator. Store coated plates insealed bag at 4° C. until used.

2. Tyrosine Kinase Reaction:

-   -   Prepare inhibitor solutions at a 4× concentration in 20% DMSO in        water.    -   Prepare reaction buffer    -   Prepare enzyme solution so that desired units are in 50 μl, e.g.        for KDR make to 1 ng/μl for a total of 50 ng per well in the        reactions. Store on ice.    -   Make 4×ATP solution to 20 μM from 100 mM stock in water. Store        on ice    -   Add 50 μl of the enzyme solution per well (typically 5-50 ng        enzyme/well depending on the specific activity of the kinase)    -   Add 25 μl 4× inhibitor    -   Add 25 μl 4×ATP for inhibitor assay    -   Incubate for 10 minutes at room temperature    -   Stop reaction by adding 50 μl 0.05N HCl per well    -   Wash plate        **Final Concentrations for Reaction: 5 μM ATP, 5% DMSO        3. Antibody Binding    -   Dilute 1 mg/ml aliquot of PY20-HRP (Pierce) antibody (a        phosphotyrosine antibody) to 50 ng/ml in 0.1% BSA in PBS by a 2        step dilution (100×, then 200×)    -   Add 100 μl Ab per well. Incubate 1 hr at room temp. Incubate 1        hr at 4° C.

Wash 4× plate

4. Color Reaction

-   -   Prepare TMB substrate and add 100 μl per well    -   Monitor OD at 650 nm until 0.6 is reached    -   Stop with 1M Phosphoric acid. Shake on plate reader.    -   Read OD immediately at 450 nm

Optimal incubation times and enzyme reaction conditions vary slightlywith enzyme preparations and are determined empirically for each lot.

For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mMMnCl₂, 20 mM MgCl₂, 5 mM DTT, 0.2% BSA, 200 mM NaVO₄ under the analogousassay conditions.

Compounds of formulas 1-109 may have therapeutic utility in thetreatment of diseases involving both identified, including those notmentioned herein, and as yet unidentified protein tyrosine kinases whichare inhibited by compounds of formulas 1-109.

Cdc2 Source

The human recombinant enzyme and assay buffer may be obtainedcommercially (New England Biolabs, Beverly, Mass. USA) or purified fromknown natural or recombinant sources using conventional methods.

Cdc2 Assay

A protocol that can be used is that provided with the purchased reagentswith minor modifications. In brief, the reaction is carried out in abuffer consisting of 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mMDTT, 0.01% Brij, 5% DMSO and 10 mM MgCl₂ (commercial buffer)supplemented with fresh 300 μM ATP (31 μCi/ml) and 30 μg/ml histone typeIIIss final concentrations. A reaction volume of 80 μL, containing unitsof enzyme, is run for 20 minutes at 25 degrees C. in the presence orabsence of inhibitor. The reaction is terminated by the addition of 120μL of 10% acetic acid. The substrate is separated from unincorporatedlabel by spotting the mixture on phosphocellulose paper, followed by 3washes of 5 minutes each with 75 mM phosphoric acid. Counts are measuredby a betacounter in the presence of liquid scintillant.

PKC Kinase Source

The catalytic subunit of PKC may be obtained commercially (Calbiochem).

PKC Kinase Assay

A radioactive kinase assay is employed following a published procedure(Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A.,Nishizuka, Y. Biochemical and Biophysical Research Communication 3:166,1220-1227 (1990)). Briefly, all reactions are performed in a kinasebuffer consisting of 50 mM Tris-HCl pH7.5, 11 mM MgCl₂, 2 mM DTT, 1 mMEGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and ³³P ATP (8Ci/mM). Compoundand enzyme are mixed in the reaction vessel and the reaction isinitiated by addition of the ATP and substrate mixture. Followingtermination of the reaction by the addition of 10 μL stop buffer (5 mMATP in 75 mM phosphoric acid), a portion of the mixture is spotted onphosphocellulose filters. The spotted samples are washed 3 times in 75mM phosphoric acid at room temperature for 5 to 15 minutes.Incorporation of radiolabel is quantified by liquid scintillationcounting.

Erk2 Enzyme Source

The recombinant murine enzyme and assay buffer may be obtainedcommercially (New England Biolabs, Beverly Mass. USA) or purified fromknown natural or recombinant sources using conventional methods.

Erk2 Enzyme Assay

In brief, the reaction is carried out in a buffer consisting of 50 mMTris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl₂(commercial buffer) supplemented with fresh 100 μM ATP (31 μCi/ml) and30 μM myelin basic protein under conditions recommended by the supplier.Reaction volumes and method of assaying incorporated radioactivity areas described for the PKC assay (vide supra).

Cellular Receptor PTK Assays

The following cellular assay was used to determine the level of activityand effect of the different compounds of the present invention onKDR/VEGFR2. Similar receptor PTK assays employing a specific ligandstimulus can be designed along the same lines for other tyrosine kinasesusing techniques well known in the art.

VEGF-Induced KDR Phosphorylation in Human Umbilical Vein EndothelialCells (HUVEC) as Measured by Western Blots:

1. HUVEC cells (from pooled donors) can be purchased from Clonetics (SanDiego, Calif.) and cultured according to the manufacturer directions.Only early passages (3-8) are used for this assay. Cells are cultured in100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth,England) using complete EBM media (Clonetics).

2. For evaluating a compound's inhibitory activity, cells aretrypsinized and seeded at 0.5-1.0×10⁵ cells/well in each well of 6-wellcluster plates (Costar; Cambridge, Mass.).

3. 3-4 days after seeding, plates are typically 90-100% confluent.Medium is removed from all the wells, cells are rinsed with 5-10 ml ofPBS and incubated 18-24 h with 5 ml of EBM base media with nosupplements added (i.e., serum starvation).

4. Serial dilutions of inhibitors are added in 1 ml of EBM media (25 μM,5 μM, or 1 μM final concentration to cells and incubated for one hour at37° C. Human recombinant VEGF₁₆₅ (R & D Systems) is then added to allthe wells in 2 ml of EBM medium at a final concentration of 50 ng/ml andincubated at 37° C. for 10 minutes. Control cells untreated or treatedwith VEGF only are used to assess background phosphorylation andphosphorylation induction by VEGF.

All wells are then rinsed with 5-10 ml of cold PBS containing 1 mMSodium Orthovanadate (Sigma) and cells are lysed and scraped in 200 μlof RIPA buffer (50 mM Tris-HCl) pH7, 150 mM NaCl, 1% NP-40, 0.25% sodiumdeoxycholate, 1 mM EDTA) containing protease inhibitors (PMSF 1 mM,aprotinin 1 μg/ml, pepstatin 1 μg/ml, leupeptin 1 μg/ml, Na vanadate 1mM, Na fluoride 1 mM) and 1 μg/ml of Dnase (all chemicals from SigmaChemical Company, St Louis, Mo.). The lysate is spun at 14,000 rpm for30 min, to eliminate nuclei.

Equal amounts of proteins are then precipitated by addition of cold(−20° C.) Ethanol (2 volumes) for a minimum of 1 hour or a maximum ofovernight. Pellets are reconstituted in Laemli sample buffer containing5%-mercaptoethanol (BioRad; Hercules, Calif.) and boiled for 5 min. Theproteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5 mmNovex, San Diego, Calif.) and transferred onto a nitrocellulose membraneusing the Novex system. After blocking with bovine serum albumin (3%),the proteins are probed overnight with anti-KDR polyclonal antibody(C20, Santa Cruz Biotechnology; Santa Cruz, Calif.) or withanti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology,Lake Placid, N.Y.) at 4° C. After washing and incubating for 1 hour withHRP-conjugated F(ab)₂ of goat anti-rabbit or goat-anti-mouse IgG thebands are visualized using the emission chemiluminescence (ECL) system(Amersham Life Sciences, Arlington Heights, Ill.).

In Vivo Uterine Edema Model

This assay measures the capacity of compounds to inhibit the acuteincrease in uterine weight in mice which occurs in the first few hoursfollowing estrogen stimulation. This early onset of uterine weightincrease is known to be due to edema caused by increased permeability ofuterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993),133:829-837) demonstrated a close temporal relationship ofestrogen-stimulated uterine edema with increased expression of VEGF mRNAin the uterus. These results have been confirmed by the use ofneutralizing monoclonal antibody to VEGF which significantly reduced theacute increase in uterine weight following estrogen stimulation (WO97/42187). Hence, this system can serve as a model for in vivoinhibition of VEGF signalling and the associated hyperpermeability andedema.

Materials: All hormones can be purchased from Sigma (St. Louis, Mo.) orCal Biochem (La Jolla, Calif.) as lyophilized powders and preparedaccording to supplier instructions. Vehicle components (DMSO, CremaphorEL) can be purchased from Sigma (St. Louis, Mo.). Mice (Balb/c, 8-12weeks old) can be purchased from Taconic (Germantown, N.Y.) and housedin a pathogen-free animal facility in accordance with institutionalAnimal Care and Use Committee Guidelines.

Method:

Day 1: Balb/c mice are given an intraperitoneal (i.p.) injection of 12.5units of pregnant mare's serum gonadotropin (PMSG).

Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) i.p.Day 4: Mice are randomized and divided into groups of 5-10. Testcompounds are administered by i.p., i.v. or p.o. routes depending onsolubility and vehicle at doses ranging from 1-100 mg/kg. Vehiclecontrol group receive vehicle only and two groups are left untreated.

Thirty minutes later, experimental, vehicle and 1 of the untreatedgroups are given an i.p. injection of 17-estradiol (500 mg/kg). After2-3 hours, the animals are sacrificed by CO₂ inhalation. Following amidline incision, each uterus was isolated and removed by cutting justbelow the cervix and at the junctions of the uterus and oviducts. Fatand connective tissue were removed with care not to disturb theintegrity of the uterus prior to weighing (wet weight). Uteri areblotted to remove fluid by pressing between two sheets of filter paperwith a one liter glass bottle filled with water. Uteri are weighedfollowing blotting (blotted weight). The difference between wet andblotted weights is taken as the fluid content of the uterus. Mean fluidcontent of treated groups is compared to untreated or vehicle treatedgroups. Significance is determined by Student's test. Non-stimulatedcontrol group is used to monitor estradiol response.

Certain compounds of this invention which are inhibitors of angiogenicreceptor tyrosine kinases can also be shown active in a Matrigel implantmodel of neovascularization. The Matrigel neovascularization modelinvolves the formation of new blood vessels within a clear marble ofextracellular matrix implanted subcutaneously which is induced by thepresence of proangiogenic factor producing tumor cells (for examplessee: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528; Anat.Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vasc.Biol. (1995), 15(11), 1857-6). The model preferably runs over 3-4 daysand endpoints include macroscopic visual/image scoring ofneovascularization, microscopic microvessel density determinations, andhemoglobin quantitation (Drabkin method) following removal of theimplant versus controls from animals untreated with inhibitors. Themodel may alternatively employ bFGF or HGF as the stimulus.

The compounds of the present invention may be used in the treatment ofprotein kinase-mediated conditions, such as benign and neoplasticproliferative diseases and disorders of the immune system. Such diseasesinclude autoimmune diseases, such as rheumatoid arthritis, thyroiditis,type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory boweldisease, Crohn's disease, myasthenia gravis and systemic lupuserythematosus; psoriasis, organ transplant rejection (e.g., kidneyrejection, graft versus host disease), benign and neoplasticproliferative diseases, human cancers such as lung, breast, stomach,bladder, colon, pancreatic, ovarian, prostate and rectal cancer andhematopoietic malignancies (leukemia and lymphoma), glioblastoma,infantile hemangioma, and diseases involving inappropriatevascularization (for example diabetic retinopathy, retinopathy ofprematurity, choroidal neovascularization due to age-related maculardegeneration, and infantile hemangiomas in human beings). Suchinhibitors may be useful in the treatment of disorders involving VEGFmediated edema, ascites, effusions, and exudates, including for examplemacular edema, cerebral edema, acute lung injury and adult respiratorydistress syndrome (ARDS). In addition, the compounds of the inventionmay be useful in the treatment of pulmonary hypertension, particularlyin patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg.2001, 122 (1), 65-73).

Synthetic Methods

Abbreviations which have been used in the descriptions of the scheme andthe examples that follow are: AIBN for2,2′-azobis(2-methylpropionitrile); THF for tetrahydrofuran; MTBE formethyl tert-butyl ether, PPh₃ for triphenylphosphine; o-tol₃P fortri-o-tolylphosphine; dppf for diphenylphosphinoferrocene; DMF forN,N-dimethylformamide; DME for 1,2-dimethoxyethane; NBS forN-bromosuccinimide; NMP for N-methylpyrrolidinone; DMSO fordimethylsulfoxide; LDA for lithium diisopropylamide; TFA fortrifluoroacetic acid; min for minutes; TBTU forO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate; andDEAD for diethyl azodicarboxylate.

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. The groups A, X, R¹, R², R³, R⁴, R⁵, and R⁶are as defined above unless otherwise noted below.

This invention is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes.Preparation of the compounds of the invention by metabolic processesinclude those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Scheme 1 shows the synthesis of compounds of formula (4). Compounds offormula (3) can be reacted with an appropriately substituted isocyanate(R⁶NCO) to provide compounds of formula (4). Examples of solvents usedin these reactions include THF, dichloromethane, and MTBE. The reactionis typically conducted at a temperature of about 0° C. to about 25° C.for about 1 hour to about 14 hours.

Compounds of formula (Ia) can be prepared following the proceduresdescribed in Scheme 2. Compounds of formula (5) can be converted tocompounds of formula (6) by treatment with hydrazine. Examples ofsolvents include n-butanol, ethanol, n-pentanol, and n-hexanol. Thereaction is typically conducted at about 80° C. to about 120° C. forabout 2 to about 12 hours. Compounds of formula (6) where R⁹ is hydrogencan be converted to compounds of formula (6) where R⁹ is alkenyl,alkoxyalkyl, alkyl, heterocyclylalkyl, hydroxyalkyl, or(NR^(a)R^(b))alkyl by treatment with the appropriately substitutedalkylating agent in the presence of a base under conditions known tothose of ordinary skill in the art.

Conversion of compounds of formula (6) to compounds of formula (Ia) canbe accomplished by treatment with compounds of formula (7) in thepresence of a palladium catalyst and a base. Representative palladiumcatalysts include Pd(PPh₃)₄, Pd(o-tol₃P)₂Cl₂, PdCl₂(dppf), andPdCl₂(dppf).CH₂Cl₂. Examples of bases include sodium carbonate, cesiumcarbonate, and potassium carbonate. Solvents typically used in thesereactions include DMF, DME, toluene, ethanol, water, and mixturesthereof. The reaction is typically conducted at temperatures betweenabout 60° C. and about 130° C. (optionally in a microwave for about 5 toabout 25 minutes) for about 4 to about 24 hours.

As shown in Scheme 3, compounds of formula (8) can be converted tocompounds of formula (9) by treatment with NBS in the presence of aradical initiator such as benzoyl peroxide AIBN. Examples of solventsused in this reaction include CCl₄, benzene, and CHCl₃. The reaction istypically conducted at about 60 to about 80° C. for about 4 to about 48hours.

Compounds of formula (9) can be converted to compounds of formula (5a)by treatment with a nucleophile (Z) (for example, an amine or analcohol). Examples of solvents used in these reactions include THF, DMF,NMP, and DME. The reaction is typically conducted at about 20° C. toabout 60° C. for about 12 to about 24 hours.

Conversion of compounds of formula (5a) to compounds of formula (6a) canbe accomplished by the methods described in Scheme 2.

Scheme 4 shows the synthesis of compounds of formula (Ib). Compounds offormula (6) (prepared by the methods described in Scheme 2) can beconverted to compounds of formula (10) by treatment with anappropriately substituted borane or other organometallic reagent such asa stannane or organozinc reagent in the presence of a palladium catalystand optionally a base. Representative palladium catalysts includePd(PPh₃)₄, Pd(o-tol₃P)₂Cl₂, PdCl₂(dppf), and PdCl₂(dppf).CH₂Cl₂.Examples of bases include sodium carbonate, cesium carbonate, andpotassium carbonate. Solvents typically used in these reactions includeDMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction istypically conducted at temperatures between about 60° C. and about 130°C. for about 4 to about 24 hours.

Compounds of formula (10) can be converted to compounds of formula (Ib)by treatment with the appropriately substituted electrophile to generateL (i.e., an isocyanate of formula R⁶NCO). Examples of solvents includedichloromethane, chloroform, THF, DMF, and MTBE. The reaction istypically conducted at about −5° C. to about 25° C. for about 12 toabout 24 hours.

As shown in Scheme 5, compounds of formula (11) can be reacted with thecompound of formula (12), a palladium catalyst, and potassium acetate,then treated with compounds of formula (6) in the presence of apalladium catalyst and a base to provide compounds of formula (Ib).Representative palladium catalysts include Pd(PPh₃)₄, Pd(o-tol₃P)₂Cl₂,PdCl₂(dppf), and PdCl₂(dppf) CH₂Cl₂. Examples of bases include sodiumcarbonate, cesium carbonate, and potassium carbonate. Solvents typicallyused in these reactions include DMF, DME, toluene, ethanol, water, andmixtures thereof. The reaction is typically conducted at temperaturesbetween about 60° C. and about 130° C. for about 4 to about 24 hours.

The synthesis of compounds of formula (Ic) is shown in Scheme 6.Compounds of formula (13) can be reacted with the compound of formula(12) then with compounds of formula (6) using the conditions describedin Scheme 5 to provide compounds of formula (14). Compounds of formula(14) can be hydrolyzed to compounds of formula (15) using conditionsknown to those of ordinary skill in the art (i.e., KOH). Compounds offormula (15) can be converted to compounds of formula (Ic) by treatmentwith an appropriately substituted amine in the presence of a couplingagent under conditions known to those of ordinary skill in the art.

Compounds of formula (Id) can be prepared as described in Scheme 7.Compounds of formula (16) can be converted to compounds of formula (17)using the conditions described in Schemes 2 and 4. Compounds of formula(17) can be converted to compounds of formula (18) (where L² is analkenyl group and R^(d) is (NR^(a)R^(b))carbonyl or alkoxycarbonyl) bytreatment with a palladium catalyst and a base such as triethylamine ordiisopropylethylamine. Examples of solvents include THF and 1,4-dioxane.The reaction is typically conducted at about 80 to about 150° C. forabout 30 minutes to about 6 hours.

Conversion of compounds of formula (18) to compounds of formula (19) canbe accomplished by methods known to those of ordinary skill in the art.Compounds of formula (19) can be converted to compounds of formula (Id)by the methods described in Scheme 4.

Scheme 8 shows the synthesis of compounds of formula (Ie). Compounds offormula (21) (where Q is Br or J) can be reacted with the compound offormula (22) in the presence of potassium tert-butoxide to providecompounds of formula (23). Examples of solvents used in this reactioninclude DMF, DME, and NMP. The reaction is typically conducted at about20° C. to about 35° C. for about 15 minutes to about 12 hours.

Compounds of formula (23) can be coupled with compounds of formula (24)using the conditions described in Schemes 2, 4, and 7 to providecompounds of formula (Ie).

The present invention will now be described in connection with certainpreferred embodiments which are not intended to limit its scope. On thecontrary, the present invention covers all alternatives, modifications,and equivalents as can be included within the scope of the claims. Thus,the following examples, which include preferred embodiments, willillustrate the preferred practice of the present invention, it beingunderstood that the examples are for the purposes of illustration ofcertain preferred embodiments and are presented to provide what isbelieved to be the most useful and readily understood description of itsprocedures and conceptual aspects.

Compounds of the invention were named by ACD/ChemSketch version 5.0(developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada).

Example 1 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaExample 1A 4-iodo-1H-indazol-3-amine

A mixture of 2-fluoro-6-iodobenzonitrile (2 g, 8.1 mmol) and hydrazinehydrate (4 mL) in n-butanol (40 mL) was heated to 105-110° C. for 5hours, cooled to room temperature, poured into water, and extractedtwice with ethyl acetate. The combined extracts were washed with waterand brine, dried (MgSO₄), filtered, and concentrated to provide 1.88 gof the desired product. R_(f)=0.25 (5% methanol/dichloromethane).

Example 1BN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

A 0° C. mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.03 g, 23 mmol)and 1-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF (90 mL) wasstirred at room temperature for 1 hour, concentrated, suspended inacetonitrile, and filtered. The filter cake was dried to provide 8.09 gof the desired product.

Example 1C N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

A mixture of Example 1A (60 mg, 0.24 mmol), Example 1B (103 mg, 0.29mmol) and Na₂CO₃ (64 mg, 0.6 mmol) under a nitrogen atmosphere wastreated with DME (8 mL), water (2 mL), and Pd(PPh₃)₄ (14 mg, 0.012mmol). The mixture was purged with bubbling nitrogen for 2 minutes,heated to 80-90° C. for about 18 hours, cooled to room temperature,poured into water, and extracted twice with ethyl acetate. The combinedextracts were washed with water and brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by flash columnchromatography on silica gel with 5-8% methanol dichloromethane toprovide 56 mg (66% yield) of the desired product. MS (ESI(+)) m/e 358(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 4.33 (s, 2H),6.76-6.83 (m, 2H), 7.17 (t, J=7.80 Hz, 1H), 7.23-7.28 (m, 3H), 7.32 (s,1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.64 (s, 1H),8.79 (s, 1H), 11.70 (s, 1H).

Example 2N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3,5-dimethoxyphenyl)urea

The desired product was prepared by substituting1-isocyanato-3,5-dimethoxy-benzene for 1-isocyanato-3-methylbenzene inExamples 1B-C. ¹H NMR (300 MHz, DMSO-d₆) δ 3.73 (s, 6H), 4.33 (s, 2H),6.15 (t, J=2.20 Hz, 1H), 6.70 (d, J=2.03 Hz, 2H), 6.78 (dd, J=5.76, 2.37Hz, 1H), 7.22-7.31 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.58 (d, J=8.81 Hz,2H), 8.73 (s, 1H), 8.78 (s, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 404(M+H)⁺.

Example 3 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-chloro-3-isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the crudeproduct by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at aflow rate of 40 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ 6.89 (dd, J=6.44,1.70 Hz, 1H), 7.03 (m, 1H), 7.28-7.38 (m, 4H), 7.42 (d, J=8.81 Hz, 2H),7.61 (d, J=8.82 Hz, 2H), 7.74 (m, 1H), 9.00 (s, 1H), 9.03 (s, 1H); MS(ESI(+)) m/e 378 (M+H)⁺; Anal. calcd. for C₂₀H₁₆ClN₅O.CF₃CO₂H: C, 52.76;H, 3.62; N, 13.98. Found: C, 52.40; H, 3.50; N, 13.86.

Example 4N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-3-(trifluoromethyl)benzene for1-isocyanato-3-methylbenzene in Examples 1B-C and purifying the productby preparative HPLC using the conditions described in Example 3. ¹H NMR(300 MHz, DMSO-d₆) δ 6.86 (dd, J=6.10, 2.03 Hz, 1H), 7.29-7.35 (m, 3H),7.42 (d, J=8.81 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H), 7.58-7.65 (m, 3H),8.05 (s, 1H), 9.01 (s, 1H), 9.16 (s, 1H); MS (ESI(+)) m/e 412 (M+H)⁺;Anal. calcd. for C₂₁H₁₆F₃N₅O.0.7CF₃CO₂H: C, 54.77; H, 3.43; N, 14.26.Found: C, 54.64; H, 3.32; N, 14.12.

Example 5N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 5AN-(2-fluoro-5-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

A 0° C. mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.5 g, 2.28mmol) and 1-fluoro-2-isocyanato-4-methylbenzene (0.297 mL, 2.28 mmol) indichloromethane (15 mL) was allowed to gradually warm to roomtemperature and stirred overnight. The resulting suspension was dilutedwith hexanes resulting in the formation of more precipitate, which wascollected by filtration to provide 0.68 g of the desired product. MS(ESI(+)) m/e 370.7 (M+H)⁺.

Example 5BN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

A mixture of Example 1A (80 mg, 0.32 mmol), Example 5A (144 mg, 0.39mmol) and Na₂CO₃ (58 mg) in DME (3 mL) and water (1 mL) was degassedwith nitrogen for 2 minutes, treated with Pd(PPh₃)₄ (19 mg, 0.0161mmol), and degassed with nitrogen for another 2 minutes. The vial wascapped and heated to 160° C. for 10 minutes with stirring in a SmithSynthesizer microwave oven (at 300 W). The reaction was concentrated andthe residue was purified by HPLC using the conditions in Example 3 toprovide 63 mg of the desired product as the trifluoroacetate salt. ¹HNMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 6.78-6.85 (m, 1H), 6.87 (dd,J=6.10, 1.70 Hz, 1H), 7.12 (dd, J=11.53, 8.48 Hz, 1H), 7.30-7.39 (m,2H), 7.42 (d, J=8.81 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80,2.37 Hz, 1H), 8.54 (d, J=2.71 Hz, 1H), 9.23 (s, 1H); MS (ESI(+)) m/e 376(M+H)⁺; Anal calcd. for C₂₁H₁₈FN₅O.0.8CF₃CO₂H: C, 58.17; H, 4.06; N,15.01. Found: C, 58.17; H, 4.29; N, 15.12.

Example 6N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crudeproduct as described in Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.33 (s,2H), 6.79 (dd, J=5.26, 2.54 Hz, 1H), 7.24-7.31 (m, 2H), 7.42 (m, 3H),7.52 (m, 1H), 7.61 (d, J=8.48 Hz, 2H), 8.65 (dd, J=7.29, 2.20 Hz, 1H),8.96 (d, J=3.05 Hz, 1H), 9.32 (s, 1H), 11.72 (s, 1H); MS (ESI(+)) m/e430 (M+H)⁺.

Example 7 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-bromo-3-isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz, DMSO-d₆)δ 6.87 (dd, J=6.10, 1.70 Hz, 1H), 7.13-7.18 (m, 1H), 7.25 (t, J=7.97 Hz,1H), 7.31-7.26 (m, 3H), 7.42 (d, J=8.82 Hz, 2H), 7.61 (d, J=8.48 Hz,2H), 7.88 (t, J=1.86 Hz, 1H), 8.99 (s, 1H); MS (ESI(−)) m/e 420, 422(M−H)⁻.

Example 8N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-bromo-4-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 2-bromo-4-isocyanato-1-methylbenzene for1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz, DMSO-d₆)δ 2.33 (s, 3H), 6.88 (dd, J=6.10, 1.70 Hz, 1H), 7.25-7.50 (m, 7H), 7.61(d, J=8.48 Hz, 2H), 8.85 (s, 1H), 8.93 (s, 1H); MS (ESI(−)) m/e 434, 435(M−H)⁻.

Example 9 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-ethyl-3-isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz, DMSO-d₆)δ 1.19 (t, J=7.63 Hz, 3H), 2.58 (q, J=7.68 Hz, 2H), 6.81-6.88 (m, 2H),7.19 (t, J=7.80 Hz, 1H), 7.25-7.36 (m, 4H), 7.40 (d, J=8.48 Hz, 2H),7.60 (d, J=8.81 Hz, 2H), 8.70 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 372(M+H)⁺.

Example 10 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crudeproduct as described in Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.33 (s,2H), 6.78 (dd, J=5.42, 2.37 Hz, 1H), 6.98 (t, J=7.29 Hz, 1H), 7.28 (m,4H), 7.39 (d, J=8.81 Hz, 2H), 7.48 (d, J=7.46 Hz, 2H), 7.59 (d, J=8.82Hz, 2H), 8.72 (s, 1H), 8.81 (s, 1H), 11.70 (s, 1H); MS (ESI(+)) m/e 344(M+H)⁺.

Example 11N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea

The desired product was prepared by substituting2-fluoro-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzenein Examples 5A-B and purifying the crude product as described in Example1C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.17 (s, 3H), 4.33 (s, 2H), 6.78 (dd,J=5.42, 2.71 Hz, 1H), 7.05 (dd, J=8.14, 2.03 Hz, 1H), 7.17 (t, J=8.65Hz, 1H), 7.23-7.30 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.45 (dd, J=12.54,2.03 Hz, 1H), 7.58 (d, J=8.81 Hz, 2H), 8.84 (s, 2H), 11.70 (s, 1H); MSESI(+)) m/e 376 (M+H)⁺.

Example 12 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluorophenyl)urea

The desired product was prepared by substituting1-fluoro-2-isocyanatobenzene for 1-isocyanato-3-methylbenzene inExamples 5A-B and purifying the crude product as described in Example1C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.33 (s, 2H), 6.79 (dd, J=5.42, 2.71 Hz,1H), 6.97-7.06 (m, 1H), 7.16 (t, J=7.63 Hz, 1H), 7.22-7.30 (m, 3H), 7.41(d, J=8.48 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H), 8.18 (m, 1H), 8.61 (d,J=2.37 Hz, 1H), 9.22 (s, 1H), 11.71 (s, 1H); MS (ESI(+)) m/e 362 (M+H)⁺.

Example 13 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(4-fluorophenyl)urea

The desired product was prepared by substituting1-fluoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene inExamples 5A-B and purifying the crude product as described in Example1C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.33 (s, 2H), 6.78 (dd, J=5.43, 2.37 Hz,1H), 7.13 (t, J=8.99 Hz, 2H), 7.22-7.29 (m, 2H), 7.39 (d, J=8.48 Hz,2H), 7.49 (m, 2H), 7.59 (d, J=8.82 Hz, 2H), 8.80 (d, J=15.60 Hz, 2H),11.70 (s, 1H); MS (ESI(+)) 362 (M+H)⁺.

Example 14 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene inExamples 5A-B and purifying the crude product as described in Example1C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.33 (s, 2H), 6.75-6.83 (m, 2H), 7.15(m, 1H), 7.23-7.36 (m, 3H), 7.40 (d, J=8.48 Hz, 2H), 7.52 (m, 1H), 7.59(d, J=8.48 Hz, 2H), 8.89 (s, 1H), 8.97 (s, 1H), 11.71 (s, 1H); MS(ESI(+)) m/e 362 (M+H)⁺.

Example 15N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)ureaExample 15A 2-fluoro-6-iodo-3-methylbenzoic acid

A −78° C. solution of 2-fluoro-4-iodo-1-methylbenzene (25 g, 105.9 mmol)in THF (200 mL) was treated dropwise with LDA (2M solution in THF, 58.5mL, 116 mmol), stirred at −78° C. for 1 hour, treated with excesspowdered dry ice, stirred at −78° C. for 30 minutes, and warmed to roomtemperature gradually over about 18 hours. The mixture was concentratedand the residue was partitioned between 4N NaOH and diethyl ether. Theaqueous phase was adjusted to pH 2 with 2N HCl and extracted three timeswith ethyl acetate. The combined extracts were washed with water andbrine, dried (MgSO₄), filtered, and concentrated to provide 19.4 g (66%yield) of the desired product. MS (ESI(+)) m/e 279 (M+H)⁺.

Example 15B 2-fluoro-6-iodo-3-methylbenzamide

A solution of Example 15A (19.3 g, 69.1 mmol) in thionyl chloride (60mL) was heated to 80° C. for 3 hours, cooled to room temperature, andconcentrated. The residue was dissolved in THF (100 mL), cooled to 0°C., treated with concentrated NH₄OH (80 mL), stirred at room temperaturefor about 18 hours, and concentrated. The concentrate was suspended inwater and filtered. The filter cake was washed with water and dried toprovide 18.67 g of the desired product. MS (CI/NH₃) m/e 280 (M+H)⁺.

Example 15C 2-fluoro-6-iodo-3-methylbenzonitrile

A solution of Example 15B (18.6 g, 66.7 mmol) in DMF (190 mL) wastreated dropwise with thionyl chloride (24 mL, 333 mmol), heated to 115°C. for 16 hours, cooled to room temperature, poured into ice, andextracted three times with ethyl acetate. The combined extracts werewashed with water and brine, dried (MgSO₄), filtered, and concentrated.The concentrate was purified by flash column chromatography on silicagel with 25% ethyl acetate/hexanes to provide 12.35 g (71% yield) of thedesired product. MS (CI/NH₃) m/e 279 (M+NH₄)⁺.

Example 15D 3-(bromomethyl)-2-fluoro-6-iodobenzonitrile

A mixture of Example 15C (8.0 g, 30.6 mmol), NBS (6.54 g, 36.78 mmol),and benzoyl peroxide (0.5 g) in CCl₄ (100 mL) was heated to reflux for36 hours during which time additional NBS (9 g) and benzoyl peroxide(1.5 g) was added in 3 portions. The suspension was filtered and thefiltrate was concentrated. The residue was purified by flash columnchromatography on silica gel with 20% ethyl acetate/hexanes to provide4.83 g (46% yield) of the desired product. R_(f)=0.27 (20% ethylacetate/hexanes).

Example 15E 2-fluoro-6-iodo-3-(4-morpholinylmethyl)benzonitrile

A solution of Example 15D (710 mg, 2.09 mmol) and morpholine (0.546 mL,6.25 mmol) in DMF (8 mL) was stirred at room temperature overnight,poured into water, and extracted twice with ethyl acetate. The combinedextracts were washed with water and brine, dried (MgSO₄), filtered, andconcentrated to provide 0.71 g of the desired product. R_(f)=0.4 (ethylacetate).

Example 15F 4-iodo-7-(4-morpholinylmethyl)-1H-indazol-3-amine

The desired product was prepared by substituting Example 15E for2-fluoro-6-iodobenzonitrile in Example 1A. R_(f)=0.18 (ethyl acetate).

Example 15G 4-(4-aminophenyl)-7-(4-morpholinylmethyl)-1H-indazol-3-amine

The desired product was prepared by substituting Example 15F and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example 1Aand 1B, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.42(d, J=4.07 Hz, 4H), 3.58 (m, 4H), 3.65 (s, 2H), 4.36 (s, 2H), 5.24 (s,2H), 6.66 (dd, J=7.80, 4.41 Hz, 3H), 7.12 (m, 3H), 11.45 (s, 1H); MS(ESI(+)) m/e 324 (M+H)⁺.

Example 15HN-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)urea

A solution of Example 15G (50 mg, 0.155 mmol) in dichloromethane wascooled to 0° C., treated with 1-fluoro-3-isocyanatobenzene (0.021 mL),stirred at room temperature overnight, and concentrated. The concentratewas purified by preparative HPLC on a Waters Symmetry C8 column (25mm×100 mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at aflow rate of 40 mL/min to provide 24 mg of the desired product as thetrifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d₆) δ 3.20-4.20 (m, 8H),4.56 (s, 2H), 6.79 (m, 1H), 6.92 (d, J=7.12 Hz, 1H), 7.16 (m, 1H), 7.32(m, 1H), 7.42 (m, 3H), 7.52 (m, 1H), 7.63 (d, J=8.81 Hz, 2H), 9.12 (s,1H), 9.16 (s, 1H); MS (ESI(+)) m/e 461 (M+H)⁺.

Example 16N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-3-methylbenzene for1-fluoro-3-isocyanatobenzene in Example 15H. ¹H NMR (300 MHz, DMSO-d₆) δ2.29 (s, 3H), 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.80 (d, J=7.12 Hz, 1H),6.92 (d, J=7.12 Hz, 1H), 7.17 (t, J=7.80 Hz, 2H), 7.27 (d, J=7.23 Hz,1H), 7.32 (s, 1H), 7.42 (m, 3H), 7.63 (d, J=8.48 Hz, 2H), 8.79 (s, 1H),8.98 (s, 1H).

Example 17N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for1-fluoro-3-isocyanatobenzene in Example 15H. ¹H NMR (300 MHz, DMSO-d₆) δ3.20-4.10 (m, 8H), 4.56 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.38-7.47 (m,4H), 7.52 (m, 1H), 7.64 (d, J=8.81 Hz, 2H), 8.64 (dd, J=7.46, 2.03 Hz,1H), 9.00 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 529 (M+H)⁺.

Example 18N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for1-fluoro-3-isocyanatobenzene in Example 15H. ¹H NMR (300 MHz, DMSO-d₆) δ3.15-4.05 (m, 8H), 4.56 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.44 (m, 4H),7.64 (d, J=8.81 Hz, 2H), 7.66 (m, 1H), 8.05 (dd, J=6.44, 2.71 Hz, 1H),9.18 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 529 (M+H)⁺.

Example 19N-{4-[3-amino-7-(4-morpholinylmethyl)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

A solution of Example 15F (80 mg, 0.22 mmol) andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea(108 mg, 0.268 mmol) in toluene (2 mL) and ethanol (1.5 mL) was treatedwith a solution of Na₂CO₃ (58 mg) in water (1 mL), degassed withnitrogen for 2 minutes, treated with Pd(PPh₃)₄ (13 mg, 0.011 mmol), anddegassed with nitrogen for another 2 minutes. The vial was capped andheated to 140-150° C. for 8-10 minutes with stirring in a SmithSynthesizer microwave oven (at 300 W). The reaction was poured intowater and extracted three times with ethyl acetate. The combinedextracts were washed with water and brine, dried (MgSO₄), filtered, andconcentrated. The concentrate was purified by HPLC using the conditionsin Example 15H to provide 55 mg of the desired product as thetrifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d₆) δ 3.10-4.08 (m, 8H),4.55 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H),7.38-7.47 (m, 3H), 7.53 (t, J=7.80 Hz, 1H), 7.58-7.69 (m, 3H), 8.06 (s,1H), 9.17 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 511 (M+H)⁺.

Example 20N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)ureaExample 20A 4-iodo-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-3-amine

The desired product was prepared by substituting 1-methylpiperazine formorpholine in Examples 15E-F. MS (ESI(+)) m/e 372 (M+H)⁺.

Example 20BN-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 20A andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.80 (s, 3H),3.00-3.50 (m, 8H), 3.97 (s, 2H), 6.85 (d, J=7.12 Hz, 1H), 7.03 (m, 1H),7.25-7.33 (m, 3H), 7.40 (d, J=8.48 Hz, 2H), 7.62 (d, J=8.48 Hz, 2H),7.74 (m, 1H), 9.14 (s, 1H), 9.17 (s, 1H); MS (ESI(+)) m/e 490 (M+H)⁺.

Example 21N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 20A andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H),2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (s, 2H), 6.80 (d, J=7.46 Hz, 1H),6.84 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.63 Hz, 1H), 7.23-7.29 (m, 2H),7.32 (s, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.61 (d, J=8.81 Hz, 2H), 8.76 (s,1H), 8.94 (s, 1H); MS (ESI(+)) m/e 470 (M+H)⁺.

Example 22N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 20A andN-(3-fluorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.79 (s, 3H),3.00-3.50 (m, 8H), 3.95 (s, 2H), 6.75-6.86 (m, 2H), 7.15 (m, 1H),7.25-7.35 (m, 2H), 7.40 (d, J=8.81 Hz, 2H), 7.52 (m, 1H), 7.62 (d,J=8.48 Hz, 2H), 9.09 (s, 1H), 9.15 (s, 1H); MS (ESI(+)) m/e 474 (M+H)⁺.

Example 23N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 20A for Example 15F in Example 19. ¹H NMR (300 MHz,DMSO-d₆) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.97 (s, 2H), 6.85 (d,J=7.46 Hz, 1H), 7.28 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.41(d, J=8.81 Hz, 2H), 7.58-7.66 (m, 3H), 8.06 (s, 1H), 8.06 (s, 1H), 9.18(s, 1H), 9.32 (s, 1H); MS (ESI(+)) m/e 524 (M+H)⁺.

Example 24N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 20A andN-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.80 (s, 3H),3.00-3.50 (m, 8H), 3.95 (d, J=2.37 Hz, 2H), 6.84 (d, J=7.12 Hz, 1H),7.28 (d, J=7.12 Hz, 1H), 7.38-7.45 (m, 3H), 7.52 (m, 1H), 7.62 (d,J=8.48 Hz, 2H), 8.64 (dd, J=7.29, 2.20 Hz, 1H), 8.99 (d, J=2.71 Hz, 1H),9.38 (s, 1H); MS (ESI(+)) m/e 542 (M+H)⁺.

Example 25N-(4-{3-amino-7-[(4-methyl-1-piperazinyl)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 20A andN-(2-fluoro-5-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H),2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.96 (s, 2H), 6.78-6.86 (m, 2H), 7.12(dd, J=11.36, 8.31 Hz, 1H), 7.27 (d, J=7.46 Hz, 1H), 7.40 (d, J=8.81 Hz,2H), 7.60 (d, J=8.48 Hz, 2H), 7.99 (dd, J=7.97, 1.86 Hz, 1H), 8.56 (d,J=2.71 Hz, 1H), 9.25 (s, 1H); MS (ESI(+)) m/e 488 (M+H)⁺.

Example 26N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)ureaExample 26A 2,3-difluoro-6-iodobenzonitrile

The desired product was prepared by substituting1,2-difluoro-4-iodobenzene for 2-fluoro-4-iodo-1-methylbenzene inExamples 15A-C.

Example 26B 4-(4-aminophenyl)-7-fluoro-1H-indazol-3-amine

The desired product was prepared by substituting Example 26A for Example15E in Examples 15F-G. MS (ESI(+)) m/e 243 (M+H)⁺.

Example 26CN-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 1-bromo-3-isocyanatobenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR(300 MHz, DMSO-d₆) δ 6.73 (dd, J=7.80, 4.07 Hz, 1H), 7.13 (dd, J=11.19,7.80 Hz, 1H), 7.16 (m, 1H), 7.25 (t, J=7.97 Hz, 1H), 7.34 (m, 1H), 7.38(d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 7.88 (t, J=2.03 Hz, 1H),8.91 (s, 1H), 8.94 (s, 1H); MS (ESI(+)) m/e 440, 442 (M+H)⁺.

Example 27N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹HNMR (300 MHz, DMSO-d₆) δ 6.74 (dd, J=7.80, 4.07 Hz, 1H), 7.03 (td,J=4.41, 2.37 Hz, 1H), 7.13 (dd, J=11.19, 7.80 Hz, 1H), 7.27-7.35 (m,2H), 7.38 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 7.74 (m, 1H),8.92 (s, 1H), 8.96 (s, 1H); MS (ESI(+)) m/e 396 (M+H)⁺.

Example 28N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 1-isocyanato-3-(trifluoromethyl)benzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. ¹H NMR (300 MHz, DMSO-d₆) δ 6.75 (dd, J=7.80, 4.07 Hz, 1H), 7.14(dd, J=11.19, 7.80 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz,2H), 7.53 (t, J=7.80 Hz, 1H), 7.61 (m, 3H), 8.04 (s, 1H), 8.98 (s, 1H),9.14 (s, 1H); MS (ESI(−)) m/e 615 (M−H)⁻.

Example 29N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 1-isocyanato-3-methylbenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹HNMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 6.75 (dd, J=7.80, 4.41 Hz, 1H),6.80 (d, J=7.46 Hz, 1H), 7.15 (m, 2H), 7.25 (m, 1H), 7.32 (s, 1H), 7.37(d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.66 (s, 1H), 8.82 (s, 1H);MS (ESI(+)) m/e 376 (M+H)⁺.

Example 30N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 3-isocyanatobenzonitrile for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR(300 MHz, DMSO-d₆) δ 6.73 (dd, J=7.80, 4.41 Hz, 1H), 7.12 (dd, J=11.19,7.80 Hz, 1H), 7.39 (d, J=8.81 Hz, 2H), 7.43 (dt, J=7.71, 1.40 Hz, 1H),7.51 (t, J=7.97 Hz, 1H), 7.60 (d, J=8.48 Hz, 2H), 7.70 (ddd, J=8.22,2.29, 1.36 Hz, 1H), 8.00 (t, J=1.70 Hz, 1H), 9.00 (s, 1H), 9.09 (s, 1H);MS (ESI(+)) m/e 387 (M+H)⁺.

Example 31N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 31A 7-[(dimethylamino)methyl]-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting N,N-dimethylamine formorpholine in Examples 15E-F. MS (ESI(+)) m/e 317 (M+H)⁺.

Example 31BN-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 31A andN-(2-fluoro-5-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H),2.82 (s, 6H), 4.51 (s, 2H), 6.82 (m, 1H), 6.91 (d, J=7.12 Hz, 1H), 7.12(dd, J=11.53, 8.48 Hz, 1H), 7.43 (d, J=8.81 Hz, 2H), 7.43 (d, J=6.78 Hz,1H), 7.62 (d, J=6.44 Hz, 2H), 7.99 (dd, J=7.80, 2.03 Hz, 1H), 8.56 (d,J=2.71 Hz, 1H), 9.26 (s, 1H); MS (ESI(+)) m/e 433 (M+H)⁺; Anal. calcd.for C₂₄H₂₅FN₆O.2.3CF₃CO₂H: C, 49.44; H, 3.96; H, 12.10. Found: C, 49.51;H, 3.78; N, 12.31.

Example 32N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 31A andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 15F andN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea,respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d₆) δ 2.82 (s, 6H),4.50 (s, 2H), 6.91 (d, J=7.12 Hz, 1H), 7.03 (m, 1H), 7.28-7.36 (m, 2H),7.40-7.45 (m, 3H), 7.63 (d, J=8.82 Hz, 2H), 7.74 (m, 1H), 9.07 (s, 1H),9.09 (s, 1H); MS (ESI(+)) m/e 435 (M+H)⁺; Anal calcd. forC₂₃H₂₃ClN₆O.2.2CF₃CO₂H: C, 47.99; H, 3.70; N, 12.25. Found: C, 48.01; H,3.41; N, 12.52.

Example 33N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 31A for Example 15F in Example 19. ¹H NMR (300 MHz,DMSO-d₆) δ 2.82 (s, 6H), 4.50 (s, 2H), 6.91 (d, J=7.46 Hz, 1H), 7.33 (d,J=7.46 Hz, 1H), 7.43 (d, J=8.48 Hz, 2H), 7.43 (d, J=7.46 Hz, 1H), 7.53(t, J=7.80 Hz, 1H), 7.61 (d, J=8.82 Hz, 1H), 7.65 (d, J=8.48 Hz, 2H),8.06 (s, 1H), 9.13 (s, 1H), 9.26 (s, 1H); MS (ESI(+)) m/e 469 (M+H)⁺.

Example 34N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaExample 34A 4-iodo-1-methyl-1H-indazol-3-amine

The desired product was prepared by substituting N-methylhydrazine forhydrazine hydrate in Example 1A. MS (ESI(+)) m/e 274 (M+H)⁺.

Example 34B 4-(4-aminophenyl)-1-methyl-1H-indazol-3-amine

The desired product was prepared by substituting Example 34A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Example 1Aand 1B, respectively, in Example 1C. MS (ESI(+)) m/e 239 (M+H)⁺.

Example 34CN-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting1-isocyanato-3-methylbenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. The resulting product was purified by flash column chromatographyon silica gel with 5-8% methanol/dichloromethane to provide the desiredproduct. MS (ESI(+)) m/e 372 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29(s, 3H), 3.79 (s, 3H), 4.39 (s, 2H), 6.79 (dd, J=6.10, 1.70 Hz, 2H),7.17 (t, J=7.80 Hz, 1H), 7.24-7.40 (m, 6H), 7.59 (d, J=8.48 Hz, 2H),8.64 (s, 1H), 8.80 (s, 1H).

Example 35 N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared as the trifluoroacetate salt bysubstituting isocyanatobenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 372 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.79 (s,3H), 6.80 (dd, J=6.55, 0.94 Hz, 1H), 6.98 (t, J=7.49 Hz, 1H), 7.39 (d,J=8.42 Hz, 2H), 7.28-7.36 (m, 4H), 7.47 (d, J=7.49 Hz, 2H), 7.59 (d,J=8.42 Hz, 2H), 8.70 (s, 1H), 8.80 (s, 1H).

Example 36N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(2-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-2-methylbenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 372 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.27 (s,3H), 3.79 (s, 3H), 4.38 (s, 2H), 6.80 (d, J=6.55 Hz, 1H), 6.96 (t,J=7.96 Hz, 1H), 7.16 (t, J=7.18 Hz, 1H), 7.19 (d, J=7.49 Hz, 1H),7.30-7.36 (m, 2H), 7.39 (d, J=8.42 Hz, 2H), 7.60 (d, J=6.55 Hz, 2H),7.84 (d, J=7.18 Hz, 1H), 7.97 (s, 1H), 9.15 (s, 1H).

Example 37N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-4-methylbenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 372 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.25 (s,3H), 3.79 (s, 3H), 6.80 (dd, J=6.55, 1.25 Hz, 1H), 7.10 (d, J=8.11 Hz,2H), 7.30-7.39 (m, 6H), 7.58 (d, J=8.42 Hz, 2H), 8.59 (s, 1H), 8.76 (s,1H).

Example 38N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methoxyphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-3-methoxybenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 388 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.74 (s,3H), 3.80 (s, 3H), 6.57 (dd, J=8.11, 2.50 Hz, 1H), 6.82 (dd, J=6.71,1.09 Hz, 1H), 6.96 (dd, J=7.96, 1.09 Hz, 1H), 7.19 (t, J=8.11 Hz, 1H),7.21 (t, J=2.18 Hz, 1H), 7.32-7.40 (m, 4H), 7.59 (d, J=8.42 Hz, 2H),8.73 (s, 1H), 8.81 (s, 1H).

Example 39N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 34B for Example 15G in Example 15H. MS (ESI(+)) m/e376 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.79 (s, 3H), 4.37 (s, 2H),6.77-6.81 (m, 1H), 6.80 (dd, J=6.55, 1.25 Hz, 1H), 7.14 (dd, J=8.11,1.25 Hz, 1H), 7.29-7.36 (m, 3H), 7.40 (d, J=8.42 Hz, 2H), 7.51 (dt,J=11.85, 2.18 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 8.87 (s, 1H), 8.94 (s,1H).

Example 40N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-chloro-3-isocyanatobenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 376 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.79 (s,3H), 4.22-4.56 (br s, 2H), 6.80 (dd, J=6.55, 1.25 Hz, 1H), 7.03 (dt,J=6.63, 2.14 Hz, 1H), 7.28-7.36 (m, 4H), 7.40 (d, J=8.42 Hz, 2H), 7.60(d, J=8.42 Hz, 2H), 7.73 (s, 1H), 8.89 (s, 1H), 8.93 (s, 1H).

Example 41N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-bromo-3-isocyanatobenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 384, 386 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.79(s, 3H), 4.40 (s, 2H), 6.80 (dd, J=6.71, 1.09 Hz, 1H), 7.16 (d, J=8.11Hz, 1H), 7.25 (t, J=7.96 Hz, 1H), 7.30-7.36 (m, 3H), 7.39 (d, J=8.42 Hz,2H), 7.59 (d, J=8.42 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.89 (s, 1H),8.91 (s, 1H).

Example 42N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-3-(trifluoromethyl)benzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 426 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.80 (s,3H), 6.81 (dd, J=6.71, 1.09 Hz, 1H), 7.31-7.37 (m, 3H), 7.40 (d, J=8.42Hz, 2H), 7.53 (t, J=7.80 Hz, 1H), 7.60 (d, J=9.05 Hz, 1H), 7.61 (d,J=8.73 Hz, 2H), 8.03 (s, 1H), 8.94 (s, 1H), 9.10 (s, 1H).

Example 43N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-fluoro-2-isocyanato-4-methylbenzene and Example 34B for1-fluoro-3-isocyanatobenzene and Example 15G, respectively, in Example15H. MS (ESI(+)) m/e 390 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.28 (s,3H), 3.80 (s, 3H), 6.81 (d, J=5.93 Hz, 2H), 7.11 (dd, J=11.39, 8.27 Hz,1H), 7.31-7.37 (m, 2H), 7.40 (d, J=8.73 Hz, 2H), 7.59 (d, J=8.42 Hz,2H), 8.00 (dd, J=7.64, 1.72 Hz, 1H), 8.52 (d, J=2.50 Hz, 1H), 9.20 (s,1H).

Example 44N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-methylphenyl)ureaExample 44A N-(4-bromo-2-fluorophenyl)-N′-(3-methylphenyl)urea

A 0° C. solution of 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) indichloromethane (10 mL) was treated dropwise with1-isocyanato-3-methylbenzene (0.71 mL, 5.26 mmol), warmed to roomtemperature, stirred for 18 hours, and filtered. The filter cake waswashed with dichloromethane and dried to provide 0.62 g of the desiredproduct. MS (ESI(−)) m/e 321 (M−H)⁻.

Example 44BN-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea

A mixture of Example 44A (100 mg, 0.31 mmol), bis(pinacolato)diboron (86mg, 0.33 mmol), Pd(dppf)Cl₂ (10 mg) and potassium acetate (270 mg) inDMF (3 mL) was heated to 80° C. for 2 hours, treated with Example 1A (64mg, 0.24 mmol), Pd(dppf)Cl₂ (6 mg), Na₂CO₃ (78 mg), and water (1 mL),heated to 80° C. for 18 hours, cooled to room temperature, andconcentrated. The concentrate was purified by preparative HPLC using theconditions described in Example 15H to provide 27 mg of the desiredproduct as the trifluoroacetate salt. MS (ESI(+)) m/e 376 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.28 (d, J=7.12 Hz, 3H), 6.82 (d, J=6.78 Hz, 1H),6.86 (t, J=3.90 Hz, 1H), 7.18 (t, J=7.63 Hz, 1H), 7.26 (d, J=8.48 Hz,2H), 7.31-7.34 (m, 3H), 7.37 (dd, J=12.21, 1.70 Hz, 1H), 8.30 (t, J=8.65Hz, 1H), 8.66 (d, J=2.37 Hz, 1H), 9.05 (s, 1H).

Example 45N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-fluoro-3-isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 380(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 6.82 (td, J=8.42, 1.87 Hz, 1H), 6.86(t, J=3.90 Hz, 1H), 7.12 (dd, J=8.11, 1.25 Hz, 1H), 7.28 (dd, J=8.27,1.72 Hz, 1H), 7.32 (m, 3H), 7.38 (dd, J=12.01, 2.03 Hz, 1H), 7.53 (dt,J=11.85, 2.18 Hz, 1H), 8.26 (t, J=8.42 Hz, 1H), 8.72 (d, J=2.18 Hz, 1H),9.33 (s, 1H).

Example 46N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-3,5-dimethylbenzene for1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 390(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.25 (s, 6H), 6.65 (s, 1H), 6.85 (t,J=3.90 Hz, 1H), 7.10 (br s, 2H), 7.26 (d, J=8.42 Hz, 1H), 7.30 (d,J=4.06 Hz, 2H), 7.36 (dd, J=12.32, 1.72 Hz, 1H), 8.29 (t, J=8.42 Hz,1H), 8.63 (d, J=2.50 Hz, 1H), 8.96 (s, 1H).

Example 47N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-isocyanato-3-ethylbenzene for1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 390(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (t, J=7.49 Hz, 3H), 2.59 (q,J=7.80 Hz, 2H), 6.85-6.87 (m, 2H), 7.21 (t, J=7.80 Hz, 1H), 7.28 (m,J=4.06 Hz, 2H), 7.31 (br s, 1H), 7.32 (br s, 1H), 7.34 (br s, 1H), 7.37(dd, J=12.17, 1.87 Hz, 1H), 8.30 (t, J=8.42 Hz, 1H), 8.64 (d, J=2.18 Hz,1H), 9.06 (s, 1H).

Example 48N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chloro-4-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 2-chloro-1-fluoro-4-isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 414(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 6.83 (dd, J=4.68, 3.12 Hz, 1H),7.24-7.40 (m, 6H), 7.84 (dd, J=6.55, 2.50 Hz, 1H), 8.23 (t, J=8.58 Hz,1H), 8.71 (s, 1H), 9.28 (s, 1H).

Example 49N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-fluoro-4-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 2-fluoro-4-isocyanato-1-methylbenzene for1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(+)) m/e 394(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.18 (s, 3H), 6.85 (m, 1H), 7.03(dd, J=8.11, 1.87 Hz, 1H), 7.19 (t, J=8.58 Hz, 1H), 7.27 (dd, J=8.27,1.72 Hz, 1H), 7.30 (br s, 1H), 7.31 (s, 1H), 7.37 (dd, J=12.17, 2.18 Hz,1H), 7.46 (dd, J=12.48, 2.18 Hz, 1H), 8.26 (t, J=8.58 Hz, 1H), 8.67 (d,J=2.18 Hz, 1H), 9.20 (s, 1H).

Example 50N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 1-chloro-3-isocyanatobenzene for1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI(−)) m/e 394(M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 6.85 (t, J=3.84 Hz, 1H), 7.05 (d,J=7.80, 1H), 7.26-7.35 (m, 5H), 7.38 (dd, J=12.17, 1.87 Hz, 1H), 7.75(t, J=2.03 Hz, 1H), 8.25 (t, J=8.42 Hz, 1H), 8.72 (d, J=2.18 Hz, 1H),9.30 (s, 1H).

Example 51N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile inExamples 1A-C. MS (ESI(−)) m/e 434, 436 (M−H)⁻; ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H), 4.46 (s, 2H), 6.73 (d, J=7.46 Hz, 1H), 6.80 (d,J=6.78 Hz, 1H), 7.17 (t, J=7.63 Hz, 1H), 7.24-7.32 (m, 2H), 7.39 (d,J=8.48 Hz, 2H), 7.50 (d, J=7.80 Hz, 1H), 7.60 (d, J=8.14 Hz, 2H), 8.64(s, 1H), 8.82 (s, 1H), 12.08 (s, 1H).

Example 52N-{4-[3-amino-1-(2-hydroxyethyl)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting 2-hydrazinoethanol forhydrazine hydrate in Examples 1A-C. MS (ESI(+)) m/e 402 (M+H)⁺; ¹H NMR(300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 3.74 (t, J=5.76 Hz, 2H), 4.20 (t,J=5.59 Hz, 2H), 6.79 (d, J=6.78 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 7.17(t, J=7.63 Hz, 1H), 7.23-7.40 (m, 6H), 7.59 (d, J=8.81 Hz, 2H), 8.65 (s,1H), 8.80 (s, 1H).

Example 53 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-phenylacetamideExample 53A methyl [4-(3-amino-1H-indazol-4-yl)phenyl]acetate

The desired product was prepared by substituting methyl(4-bromophenyl)acetate and K₃PO₄ for Example 44A and Na₂CO₃,respectively, in Example 44B. Additionally the reaction was carried ourunder anhydrous conditions. MS (ESI(+)) m/e 304 (M+H)⁺.

Example 53B [4-(3-amino-1H-indazol-4-yl)phenyl]acetic acid

A solution of Example 53A (140 mg) in 1:1 methanol/10% NaOH (1 mL) wasstirred at room temperature for 2 hours and adjusted to pH 3 with 10%HCl. The resulting precipitate was collected by filtration to provide108 mg of the desired product. MS (ESI(+)) m/e 268 (M+H)⁺.

Example 53C 2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-phenylacetamide

A mixture of Example 53B (40 mg, 015 mmol), diisopropylethylamine (0.078mL, 0.45 mmol), TBTU (57 mg, 0.18 mmol), and aniline in THF (1 mL) wasstirred for 18 hours at room temperature and concentrated. The residuewas purified by preparative HPLC using the conditions described inExample 15H to provide 15 mg of the desired product as thetrifluoroacetate salt. MS (ESI(+)) m/e 343 (M+H)⁺; ¹H NMR (300 MHz,DMSO-d₆) δ 3.74 (s, 2H), 6.84 (dd, J=5.09, 3.05 Hz, 1H), 7.02-7.07 (m,1H), 7.28-7.33 (m, 4H), 7.43-7.50 (m, 4H), 7.62 (d, J=7.80 Hz, 2H).

Example 542-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-chlorophenyl)acetamide

The desired product was prepared as the trifluoroacetate salt bysubstituting 3-chloroaniline for aniline in Example 53C. MS (ESI(+)) m/e377 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.75 (s, 1H), 6.84 (dd, J=5.30,2.50 Hz, 1H), 7.11 (dd, J=7.96, 2.03 Hz, 1H), 7.31-7.36 (m, 3H),7.44-7.49 (m, 6H), 7.85 (d, J=1.87 Hz, 1H), 10.39 (s, 1H).

Example 552-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide

The desired product was prepared as the trifluoroacetate salt bysubstituting 4-fluoro-3-methylaniline for aniline in Example 53C. MS(ESI(+)) m/e 375 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.20 (d, J=1.56 Hz,3H), 3.71 (s, 2H), 6.84 (dd, J=5.46, 2.34 Hz, 1H), 7.07 (t, J=9.20 Hz,1H), 7.31 (s, 1H), 7.32 (d, J=3.43 Hz, 1H), 7.40-7.60 (m, 3H), 7.45 (d,J=4.99 Hz, 2H), 7.54 (dd, J=7.02, 2.34 Hz, 1H), 10.16 (s, 1H).

Example 562-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetamide

The desired product was prepared by substituting3-(trifluoromethyl)aniline for aniline in Example 53C, then purifyingthe resulting product by flash column chromatography on silica gel with5-8% methanol/dichloromethane. MS (ESI(+)) m/e 411 (M+H)⁺; ¹H NMR (300MHz, DMSO-d₆) δ 3.77 (s, 2H), 4.29 (s, 2H), 6.79 (dd, J=4.41, 3.39 Hz,1H), 7.27 (s, 1H), 7.28 (d, J=1.36 Hz, 1H), 7.40-7.49 (m, 3H), 7.46 (d,J=3.39 Hz, 2H), 7.56 (t, J=7.63 Hz, 1H), 7.81 (d, J=9.83 Hz, 1H), 8.14(s, 1H), 10.57 (s, 1H), 11.74 (s, 1H).

Example 572-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide

The desired product was prepared as the trifluoroacetate salt bysubstituting 3-methylaniline for aniline in Example 53C. MS (ESI(+)) m/e357 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.27 (s, 3H), 3.72 (s, 2H), 6.83(dd, J=4.75, 3.05 Hz, 1H), 6.86 (d, J=7.46 Hz, 1H), 7.18 (t, J=7.80 Hz,1H), 7.30 (s, 1H), 7.32 (d, J=2.03 Hz, 1H), 7.39-7.49 (m, 6H), 10.13 (s,1H).

Example 58N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaExample 58A 2-fluoro-6-iodo-3-methoxybenzonitrile

The desired product was prepared by substituting2-fluoro-4-iodo-1-methoxybenzene for 2-fluoro-4-iodo-1-methylbenzene inExamples 15A-C.

Example 58B 4-(4-aminophenyl)-7-methoxy-1H-indazol-3-amine

The desired product was prepared by substituting Example 58A for Example15E in Examples 15F-G. MS (ESI(+)) m/e 290 (M+H)⁺.

Example 58CN-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 58B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting product by flash column chromatography on silicagel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 388 (M+H)⁺; ¹HNMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 3.92 (s, 3H), 4.30 (s, 2H), 6.69(d, J=7.80 Hz, 1H), 6.78 (d, J=7.79 Hz, 1H), 6.80 (d, J=7.46 Hz, 1H),7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz,2H), 7.55 (d, J=8.82 Hz, 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.86 (s, 1H).

Example 59N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 58B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting product by flash column chromatography on silicagel with 5-8% methanol/dichloromethane. MS (ESI(−)) m/e 458 (M−H)⁻; ¹HNMR (300 MHz, DMSO-d₆) δ 3.93 (s, 3H), 4.30 (s, 2H), 6.71 (d, J=7.80 Hz,1H), 6.79 (d, J=7.80 Hz, 1H), 7.38 (d, J=8.48 Hz, 2H), 7.41 (m, 1H),7.50 (d, J=10.85 Hz, 1H), 7.58 (d, J=8.82 Hz, 2H), 8.65 (dd, J=7.46,2.03 Hz, 1H), 8.95 (d, J=2.71 Hz, 1H), 9.29 (s, 1H), 11.88 (s, 1H).

Example 60 N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 374 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.94 (s, 3H), 6.75 (d,J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H), 7.29(t, J=7.95 Hz, 2H), 7.36 (d, J=8.74 Hz, 2H), 7.47 (d, J=7.49 Hz, 2H),7.57 (d, J=8.42 Hz, 2H), 8.71 (s, 1H), 8.79 (s, 1H).

Example 61N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and 1-bromo-3-isocyanatobenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 452 and 454 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.94 (s,3H), 6.73 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H), 7.16 (d, J=8.73Hz, 1H), 7.25 (t, J=8.11 Hz, 1H), 7.33 (d, J=9.36 Hz, 1H), 7.36 (d,J=8.73 Hz, 2H), 7.56 (d, J=8.74 Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.87(s, 1H), 8.92 (s, 1H).

Example 62N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and 1-isocyanato-3-ethylbenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 402 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (t, J=7.64 Hz,3H), 2.58 (q, J=7.70 Hz, 2H), 3.94 (s, 3H), 6.73 (d, J=7.49 Hz, 1H),6.82 (t, J=7.80 Hz, 2H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=7.80 Hz,1H), 7.34 (s, 1H), 7.35 (d, J=8.42 Hz, 2H), 7.56 (d, J=8.42 Hz, 2H),8.64 (s, 1H), 8.75 (s, 1H).

Example 63N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and 2-fluoro-4-isocyanato-1-methylbenzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(+)) m/e 406 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.17 (s,3H), 3.94 (s, 3H), 6.75 (d, J=7.49 Hz, 1H), 6.83 (d, J=7.80 Hz, 1H),7.05 (dd, J=8.27, 2.03 Hz, 1H), 7.17 (t, J=8.58 Hz, 1H), 7.36 (d, J=8.73Hz, 2H), 7.45 (dd, J=12.48, 1.87 Hz, 1H), 7.56 (d, J=8.73 Hz, 2H), 8.82(s, 1H), 8.83 (s, 1H).

Example 64N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 460 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.95 (s, 3H), 6.79 (d,J=7.80 Hz, 1H), 6.86 (d, J=7.80 Hz, 1H), 7.38 (d, J=8.42 Hz, 2H), 7.44(t, J=9.67 Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 7.67 (dt, J=8.66, 3.78 Hz,1H), 8.03 (dd, J=6.40, 2.65 Hz, 1H), 9.01 (s, 1H), 9.17 (s, 1H).

Example 65N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 408 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.94 (s, 3H), 6.76(d, J=7.49 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 7.02 (dt, J=6.63, 2.14 Hz,1H), 7.31 (m, 2H), 7.37 (d, J=8.74 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H),7.74 (m, 1H), 8.90 (s, 1H), 8.96 (s, 1H).

Example 66N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B and 1-isocyanato-3-(trifluoromethyl)benzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(+)) m/e 442 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.94 (s,3H), 6.76 (d, J=7.80 Hz, 1H), 6.84 (d, J=7.80 Hz, 1H), 7.32 (d, J=7.80Hz, 1H), 7.38 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H), 7.59 (d,J=8.42 Hz, 2H), 7.57-7.61 (m, 1H), 8.04 (s, 1H), 8.96 (s, 1H), 9.14 (s,1H).

Example 67N-[4-(3-amino-7-methoxy-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 58B for Example 15G in Example 15H. MS (ESI(+)) m/e392 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.94 (s, 3H), 6.77 (d, J=7.80Hz, 1H), 6.77-6.81 (m, 1H), 6.85 (d, J=7.80 Hz, 1H), 7.14 (dd, J=8.11,0.94 Hz, 1H), 7.29-7.34 (m, 1H), 7.37 (d, J=8.73 Hz, 2H), 7.51 (dt,J=11.93, 2.30 Hz, 1H), 7.57 (d, J=8.73 Hz, 2H), 8.89 (s, 1H), 8.98 (s,1H).

Example 68N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)ureaExample 68A 2-fluoro-3-hydroxy-6-iodobenzonitrile

A —78° C. solution of 2-fluoro-6-iodo-3-methoxybenzonitrile (148 mg,0.53 mmol) in dichloromethane (5 mL) was treated dropwise with BBr₃ (2.5mL, 1M in dichloromethane, 2.5 mmol), warmed to room temperature,stirred for 18 hours, poured into water, and extracted with diethylether. The extract was dried (MgSO₄), filtered, and concentrated. Theresidue was purified by flash column chromatography on silica gel with20% ethyl acetate/hexanes to provide 110 mg of the desired product. MS(ESI(−)) m/e 262 (M−H)⁻.

Example 68B 2-fluoro-6-iodo-3-(2-methoxyethoxy)benzonitrile

A mixture of Example 68A (104 mg, 0.39 mmol), 1-bromo-2-methoxyethane(0.088 mL) and K₂CO₃ (163 mg) in acetone (3 mL) was heated to 60° C. for18 hours, cooled to room temperature, and partitioned between diethylether and water. The extract was dried (MgSO₄), filtered, andconcentrated to provide 122 mg of the desired product. MS (ESI(+)) m/e334 (M+H)⁺.

Example 68C 4-(4-aminophenyl)-7-(2-methoxyethoxy)-1H-indazol-3-amine

The desired product was prepared by substituting Example 68B for Example15E in Examples 15F-G. MS (ESI(+)) m/e 299 (M+H)⁺.

Example 68DN-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 68C and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15, thenpurifying the resulting producty by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 432(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 3.35 (s, 3H), 3.76(dd, J=5.09, 3.73 Hz, 2H), 4.27 (t, J=3.05 Hz, 2H), 4.29 (s, 2H), 6.67(d, J=7.46 Hz, 1H), 6.79 (d, J=7.80 Hz, 2H), 7.16 (t, J=7.63 Hz, 1H),7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.55 (d, J=8.48 Hz,2H), 8.63 (s, 1H), 8.76 (s, 1H), 11.83 (s, 1H).

Example 69N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-phenylurea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 68C and isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 418 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 3.36 (s, 3H), 3.76 (t,J=4.41 Hz, 2H), 4.30 (t, J=4.75 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.86(d, J=7.80 Hz, 1H), 6.98 (t, J=7.29 Hz, 1H), 7.29 (t, J=7.46 Hz, 2H),7.36 (d, J=8.82 Hz, 2H), 7.47 (d, J=7.46 Hz, 2H), 7.57 (d, J=8.48 Hz,2H), 8.72 (s, 1H), 8.80 (s, 1H).

Example 70N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 68C for Example 15G in Example 15H. MS (ESI(+)) m/e436 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H),4.28-4.30 (m, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.79 (td, J=8.58, 2.18 Hz,1H), 6.85 (d, J=7.80 Hz, 1H), 7.14 (dd, J=8.27, 1.09 Hz, 1H), 7.31 (m,1H), 7.37 (d, J=8.74 Hz, 2H), 7.51 (dt, J=11.93, 2.30 Hz, 1H), 7.57 (d,J=8.42 Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).

Example 71N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 68C and 1-bromo-3-isocyanatobenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 496 and 498 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.36 (s,3H), 3.75-3.77 (m, 2H), 4.28-4.30 (m, 2H), 6.73 (d, J=7.49 Hz, 1H), 6.84(d, J=7.80 Hz, 1H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H),7.33 (dd, J=8.27, 1.09 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.57 (d, J=8.42Hz, 2H), 7.88 (t, J=1.87 Hz, 1H), 8.87 (s, 1H), 8.92 (s, 1H).

Example 72N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by as the trifluoroacetate saltsubstituting Example 68C and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 452 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.36 (s, 3H), 3.76(t, J=4.68 Hz, 2H), 4.29 (t, J=4.68 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H),6.85 (d, J=7.80 Hz, 1H), 7.02 (dt, J=6.86, 2.03 Hz, 1H), 7.30 (m, 2H),7.37 (d, J=8.42 Hz, 2H), 7.57 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 8.89 (s,1H), 8.95 (s, 1H).

Example 73N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 68C and 1-isocyanato-3-(trifluoromethyl)benzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(+)) m/e 486 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.36 (s,3H), 3.75-3.77 (m, 2H), 4.29-4.31 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.86(d, J=7.80 Hz, 1H), 7.32 (d, J=8.11 Hz, 1H), 7.38 (d, J=8.42 Hz, 2H),7.52 (t, J=7.95 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 7.58-7.61 (m, 1H),8.04 (s, 1H), 8.95 (s, 1H), 9.12 (s, 1H).

Example 74N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 68C and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 504 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.36 (s, 3H), 3.76 (t,J=4.68 Hz, 2H), 4.29 (t, J=4.68 Hz, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.85(d, J=7.80 Hz, 1H), 7.39 (d, J=8.74 Hz, 2H), 7.39-7.41 (m, 1H), 7.51 (m,1H), 7.58 (d, J=8.42 Hz, 2H), 8.64 (dd, J=7.18, 2.18 Hz, 1H), 8.93 (d,J=2.81 Hz, 1H), 9.28 (s, 1H).

Example 75N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)ureaExample 75A 2-fluoro-6-iodo-3-[2-(4-morpholinyl)ethoxy]benzonitrile

A mixture of Example 68A (250 mg, 0.95 mmol), 2-(4-morpholinyl)ethanol(0.19 mL) and triphenylphosphine on resin (630 mg, 3 mmol/g, 1.9 mmol)in THF (5 mL) was treated with DEAD (0.179 mL) and stirred at roomtemperature for about 18 hours. The mixture was filtered and thefiltrate was concentrated. The residue was purified twice by flashcolumn chromatography on silica gel, first eluting with 5%methanol/dichloromethane then with 50% ethyl acetate/hexanes to provide180 mg of the desired product. MS (ESI(+)) m/e 377 (M+H)⁺.

Example 75B4-(4-aminophenyl)-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-3-amine

The desired product was prepared by substituting Example 75A for Example15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H)⁺.

Example 75CN-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 75B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting producty by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 487(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 2.52-2.55 (m, 4H),2.79 (t, J=5.76 Hz, 2H), 3.57-3.60 (m, 4H), 4.26 (t, J=5.76 Hz, 2H),4.30 (s, 2H), 6.68 (d, J=7.46 Hz, 1H), 6.80 (d, J=7.80 Hz, 2H), 7.16 (t,J=7.80 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J=8.48 Hz, 2H),7.55 (d, J=8.82 Hz, 2H), 8.64 (s, 1H), 8.77 (s, 1H), 11.81 (s, 1H).

Example 76N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylurea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 473 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.66 (m, 2H), 3.33-4.45 (brm, 8H), 4.54 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H),6.98 (t, J=7.33 Hz, 1H), 7.29 (t, J=7.80 Hz, 2H), 7.36 (d, J=8.73 Hz,2H), 7.48 (d, J=7.49 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 8.86 (s, 1H),8.95 (s, 1H).

Example 77N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B for Example 15G in Example 15H. MS (ESI(+)) m/e491 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.66 (t, J=4.37 Hz, 2H), 3.71(br m, 8H), 4.53 (t, J=4.99 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.79 (td,J=8.42, 1.87 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (dd, J=8.27, 1.09Hz, 1H), 7.31 (m, 1H), 7.36 (d, J=8.74 Hz, 2H), 7.52 (dt, J=12.09, 2.22Hz, 1H), 7.58 (d, J=8.74 Hz, 2H), 8.97 (s, 1H), 9.06 (s, 1H).

Example 78N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-bromophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and 1-bromo-3-isocyanatobenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 551 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.66 (t, J=4.36 Hz,2H), 3.30-4.32 (br m, 8H), 4.54 (t, J=4.68 Hz, 2H), 6.75 (d, J=7.49 Hz,1H), 6.89 (d, J=7.80 Hz, 1H), 7.16 (d, J=8.73 Hz, 1H), 7.25 (t, J=7.95Hz, 1H), 7.34-7.35 (m, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz,2H), 7.89 (t, J=1.87 Hz, 1H), 9.07 (s, 1H), 9.11 (s, 1H).

Example 79N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-ethylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and 1-ethyl-3-isocyanatobenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 501 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (t, J=7.49 Hz,3H), 2.58 (q, J=7.49 Hz, 2H), 3.66 (m, 2H), 3.31-4.01 (br m, 8H), 4.53(m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.83 (d, J=7.49 Hz, 1H), 6.89 (d,J=7.80 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=8.42 Hz, 1H), 7.35(m, J=8.42 Hz, 3H), 7.58 (d, J=8.73 Hz, 2H), 8.70 (s, 1H), 8.82 (s, 1H).

Example 80N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(−))m/e 557 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 3.66 (t, J=4.68 Hz, 2H),3.32-4.20 (br m, 8H), 4.54 (t, J=4.68 Hz, 2H), 6.76 (d, J=7.49 Hz, 1H),6.89 (d, J=7.80 Hz, 1H), 7.39 (d, J=8.73 Hz, 2H), 7.41 (m, J=4.06 Hz,1H), 7.51 (t, J=8.73 Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 8.64 (dd, J=7.33,2.03 Hz, 1H), 8.97 (d, J=2.81 Hz, 1H), 9.34 (s, 1H).

Example 81N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(−))m/e 557 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 3.66 (m, 2H), 3.83 (m, 8H),4.53 (m, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.36 (d,J=8.42 Hz, 2H), 7.45 (t, J=9.67 Hz, 1H), 7.59 (d, J=8.73 Hz, 2H), 7.66(dt, J=8.74, 3.74 Hz, 1H), 8.04 (dd, J=6.40, 2.65 Hz, 1H), 9.08 (s, 1H),9.25 (s, 1H).

Example 82N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 507 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.31-4.00 (br m,8H), 3.65 (m, 2H), 4.53 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d,J=7.80 Hz, 1H), 7.01 (td, J=4.45, 2.03 Hz, 1H), 7.30 (d, J=4.99 Hz, 2H),7.35 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 7.73 (s, 1H), 9.10 (s,1H), 9.15 (s, 1H).

Example 83N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and 1-isocyanato-3-(trifluoromethyl)benzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(−)) m/e 539 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 3.66 (m,2H), 3.32-4.11 (m, 8H), 4.54 (m, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d,J=7.80 Hz, 1H), 7.31 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52(s, 1H), 7.61 (d, J=8.42 Hz, 2H), 7.62 (m, 1H), 8.06 (s, 1H), 9.18 (s,1H), 9.36 (s, 1H).

Example 84(2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}-N,N-dimethylacrylamideExample 84A 7-bromo-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting4-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile inExample 1A.

Example 84B 7-bromo-4-(4-nitrophenyl)-1H-indazol-3-amine

The desired product was prepared by substituting Example 84A and4-nitrophenylboronic acid for Example 1A and Example 1B, respectively,in Example 1C. MS (ESI(+)) m/e 333, 335 (M+H)⁺.

Example 84C(2E)-3-[3-amino-4-(4-nitrophenyl)-1H-indazol-7-yl]-N,N-dimethylacrylamide

A mixture of Example 84B (165 mg), N,N-dimethylacrylamide (0.102 mL),triethylamine (0.207 mL), and Pd(o-tol₃P)₂Cl₂ (30 mg) in THF (2 mL) in asealed tube was heated in a Smith Synthesizer microwave oven (at 300 W)to 150° C. and concentrated. The residue was purified by flash columnchromatography on silica gel with 3% methanol/dichloromethane to provide163 mg of the desired product. MS (ESI(+)) m/e 352 (M+H)⁺.

Example 84D(2E)-3-[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]-N,N-dimethylacrylamide

A solution of Example 84C (113 mg, 0.32 mmol) in a mixture of ethanol (1mL), methanol (1 mL), and THF (1 mL) was treated with iron powder (144mg) and NH₄Cl (17 mg), heated to 85° C. for 4 hours, cooled to roomtemperature, and filtered. The filtrate was partitioned between waterand ethyl acetate and the organic phase was dried (MgSO₄), filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel with 5% methanol/dichloromethane to provide 75 mg of thedesired product. MS (ESI(+)) m/e 322 (M+H)⁺.

Example 84E(2E)-3-{3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}N,N-dimethylacrylamide

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 84D and 1-isocyanato-3-methylbenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 455 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 2.97(s, 3H), 3.21 (s, 3H), 6.80 (d, J=8.14 Hz, 1H), 6.86 (d, J=7.46 Hz, 1H),7.17 (m, 1H), 7.24 (m, 2H), 7.32 (s, 1H), 7.41 (d, J=8.82 Hz, 2H), 7.61(d, J=8.81 Hz, 2H), 7.70 (d, J=7.80 Hz, 1H), 7.85 (d, J=15.60 Hz, 1H),8.65 (s, 1H), 8.83 (s, 1H).

Example 85(2E)-3-{3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}-N,N-dimethylacrylamide

The desired product was prepared by substituting Example 84D and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting producty by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane. MS (ESI(+)) m/e 475(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.97 (s, 3H), 3.21 (s, 3H), 4.44 (s,2H), 6.86 (d, J=7.46 Hz, 1H), 7.01-7.06 (m, 1H), 7.23 (d, J=15.60 Hz,1H), 7.30-7.32 (m, 2H), 7.43 (d, J=8.48 Hz, 2H), 7.61 (d, J=8.82 Hz,2H), 7.70 (d, J=7.46 Hz, 1H), 7.74 (m, 1H), 7.85 (d, J=15.60 Hz, 1H),8.96 (s, 1H), 8.98 (s, 1H), 12.17 (s, 1H).

Example 86(2E)-3-(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)-N,N-dimethylacrylamide

The desired product was prepared by substituting Example 84D and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting producty by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane. MS (ESI(−)) m/e 507(M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ 2.97 (s, 3H), 3.21 (s, 3H), 4.44 (s,2H), 6.86 (d, J=7.12 Hz, 1H), 7.23 (d, J=15.60 Hz, 1H), 7.32 (d, J=7.80Hz, 1H), 7.43 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H), 7.59 (s, 1H),7.63 (d, J=8.81 Hz, 2H), 7.70 (d, J=7.80 Hz, 1H), 7.85 (d, J=15.26 Hz,1H), 8.04 (s, 1H), 8.99 (s, 1H), 9.13 (s, 1H), 12.17 (s, 1H).

Example 87N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylureaExample 87A4-(4-aminophenyl)-7-[2-(dimethylamino)ethoxy]-1H-indazol-3-amine

The desired product was prepared by substituting2-(dimethylamino)ethanol for 2-(4-morpholinyl)ethanol in Example 75A-B.MS (ESI(+)) m/e 312 (M+H)⁺.

Example 87BN-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylurea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 87A and isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 431 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.95 (s, 6H), 3.61 (br s,2H), 4.49 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H),6.98 (t, J=7.32 Hz, 1H), 7.29 (t, J=7.93 Hz, 2H), 7.36 (d, J=8.54 Hz,2H), 7.48 (d, J=7.93 Hz, 2H), 7.59 (d, J=8.54 Hz, 2H), 8.88 (s, 1H),8.97 (s, 1H).

Example 88N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-bromophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 87A and 1-bromo-3-isocyanatobenzene for Example 15Gand 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 509 and 511 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.95 (s,6H), 3.61 (s, 2H), 4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d,J=7.63 Hz, 1H), 7.16 (d, J=8.85 Hz, 1H), 7.25 (t, J=8.09 Hz, 1H), 7.35(m, J=10.68 Hz, 1H), 7.37 (d, J=8.54 Hz, 2H), 7.60 (d, J=8.54 Hz, 2H),7.90 (t, J=1.83 Hz, 1H), 9.17 (s, 1H), 9.21 (s, 1H).

Example 89N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 87A and 1-isocyanato-3-methylbenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 445 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.29 (s, 3H), 2.95(s, 6H), 3.61 (br s, 2H), 4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.80(d, J=7.32 Hz, 1H), 6.90 (d, J=7.63 Hz, 1H), 7.16 (t, J=7.78 Hz, 1H),7.26 (d, J=8.54 Hz, 1H), 7.33 (s, 1H), 7.36 (d, J=8.54 Hz, 2H), 7.59 (d,J=8.54 Hz, 2H), 8.81 (s, 1H), 8.97 (s, 1H).

Example 90N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 87A and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(−)) m/e 463 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 2.95 (s, 6H), 3.61(br s, 2H), 4.50 (m, 2H), 6.77 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.93 Hz,1H), 7.02 (td, J=4.42, 2.14 Hz, 1H), 7.31 (m, 2H), 7.37 (d, J=8.85 Hz,2H), 7.60 (d, J=8.54 Hz, 2H), 7.75 (s, 1H), 9.14 (s, 1H), 9.20 (s, 1H).

Example 91N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)ureaExample 91A1-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)-2-pyrrolidinone

The desired product was prepared by substituting1-(2-hydroxyethyl)-2-pyrrolidinone for 2-(4-morpholinyl)ethanol inExample 75A-B. MS (ESI(+)) m/e 352 (M+H)⁺.

Example 91BN-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 91A and 1-isocyanato-3-methylbenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 485 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.93 (m, 2H), 2.24(t, J=8.14 Hz, 2H), 2.29 (s, 3H), 3.55 (m, 2H), 3.62 (m, 2H), 4.27 (t,J=5.43 Hz, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.12 Hz, 1H), 6.86(d, J=7.80 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (m, 1H), 7.32 (s, 1H),7.35 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.64 (s, 1H), 8.78 (s,1H).

Example 922-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide

The desired product was prepared by substituting Example 34A and2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-N-m-tolyl-acetamidefor Example 1A and Example 1B, respectively, in Example 53C. The crudeproduct was purified by preparative HPLC using the conditions describedin Example 3 to provide the desired product as the trifluoroacetatesalt. MS (ESI(+)) m/e 371 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.27 (s,3H), 3.72 (s, 2H), 3.80 (s, 3H), 6.82 (dd, J=6.61, 1.19 Hz, 1H), 6.86(d, J=7.46 Hz, 1H), 7.18 (t, J=7.80 Hz, 1H), 7.31-7.48 (m, 8H), 10.13(s, 1H).

Example 93N-[4-(3-amino-1H-indazol-4-yl)-2-methylphenyl]-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting 4-bromo-2-methylaniline for 4-bromo-2-fluoroaniline inExample 44A-B. MS (ESI(−)) m/e 370 (M−H)⁻; ¹H NMR (300 MHz, DMSO-d₆) δ2.29 (s, 3H), 2.33 (s, 3H), 6.80 (d, J=7.46 Hz, 1H), 6.85 (dd, J=6.10,1.70 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25-7.34 (m, 6H), 8.03 (m, 2H),9.03 (s, 1H).

Example 94N-(4-{3-amino-7-[2-(2-oxo-1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 91A and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 505 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 1.93 (m, 2H), 2.24(t, J=8.14 Hz, 2H), 3.55 (m, 2H), 3.62 (t, J=5.43 Hz, 2H), 4.27 (t,J=5.59 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.87 (d, J=8.14 Hz, 1H), 7.03(dt, J=6.53, 2.33 Hz, 1H), 7.30 (s, 1H), 7.31 (d, J=3.73 Hz, 1H), 7.37(d, J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 7.74 (d, J=1.70 Hz, 1H),8.89 (s, 1H), 8.95 (s, 1H).

Example 95N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaExample 95A 4-bromo-1,2-benzisoxazol-3-amine

A suspension of acetylhydroxamic acid (2.46 g, 32.8 mmol) and potassiumtert-butoxide (3.68 g, 32.8 mmol) in DMF (40 mL) was stirred at roomtemperature for 30 minutes, treated with 2-bromo-6-fluorobenzonitrile(4.36 g, 21.8 mmol), stirred for three hours, poured into water, andextracted three times with ethyl acetate. The combined extracts werewashed with brine, dried (MgSO₄), filtered, and concentrated. Theresidue was purified by flash column chromatography on silica gel with 5to 20% ethyl acetate/hexanes to provide 2.5 g of the desired product. MS(ESI(+)) m/e 212.9, 214.9 (M+H)⁺.

Example 95BN-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 95A for Example1A in Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ 2.29 (s, 3H), 5.22 (s,2H), 6.81 (d, J=7.12 Hz, 1H), 7.10-7.70 (m, 10H), 8.66 (s, 1H), 8.85 (s,1H); MS (ESI(+)) m/e 359 (M+H)⁺.

Example 96N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-(trifluoromethyl)phenyl]ureaExample 96AN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[2-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-2-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzenein Example 1B.

Example 96BN-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 95A and Example96A for Example 1A and Example 1B, respectively, in Example 1C. ¹H NMR(300 MHz, DMSO-d₆) δ 5.22 (s, 2H), 7.00-7.75 (m, 10H), 7.95 (d, J=7.80Hz, 1H), 8.16 (s, 1H), 9.57 (s, 1H); MS (ESI(+)) m/e 413 (M+H)⁺.

Example 97N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 95A and Example5A for Example 1A and Example 1B, respectively, in Example 1C. ¹H NMR(300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 5.22 (s, 2H), 6.75-6.85 (m, 1H),7.06-7.18 (m, 2H), 7.40-7.66 (m, 6H), 8.00 (dd, J=7.97, 1.86 Hz, 1H),8.55 (d, J=2.37 Hz, 1H), 9.25 (s, 1H); MS (ESI(+)) m/e 377 (M+H)⁺.

Example 98N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]ureaExample 98AN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzenein Example 1B.

Example 98BN-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 95A and Example98A for Example 1A and Example 1B, respectively, in Example 1C. ¹H NMR(300 MHz, DMSO-d₆) δ 5.22 (s, 2H), 7.14 (d, J=6.78 Hz, 1H), 7.33 (d,J=7.12 Hz, 1H), 7.40-7.75 (m, 8H), 8.04 (s, 1H), 9.00 (s, 1H), 9.12 (s,1H); MS (ESI(+)) m/e 413 (M+H)⁺.

Example 99N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaExample 99AN-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

The desired product was prepared by substituting1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for1-isocyanato-3-methylbenzene in Example 1B.

Example 99BN-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 95A and Example99A for Example 1A and Example 1B, respectively, in Example 1C. ¹H NMR(300 MHz, DMSO-d₆) δ 5.22 (s, 2H), 7.15 (d, J=7.12 Hz, 1H), 7.40-7.70(m, 8H), 8.64 (d, J=7.46 Hz, 1H), 8.98 (s, 1H), 9.38 (s, 1H); MS(ESI(+)) m/e 431 (M+H)⁺.

Example 100N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaExample 100A 2-fluoro-6-iodo-3-methoxybenzonitrile

The desired product was prepared by substituting2-fluoro-4-iodo-1-methoxybenzene for 2-fluoro-4-iodo-1-methylbenzene inExamples 15A-C.

Example 100B 4-iodo-7-methoxy-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 100A for2-bromo-6-fluorobenzonitrile in Example 95A.

Example 100C 4-(4-aminophenyl)-7-methoxy-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 100B forExample 15F in Example 15G. ¹H NMR (300 MHz, DMSO-d₆) δ 3.93 (s, 3H),5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d, J=8.48 Hz, 2H), 6.94 (d, J=8.14 Hz,1H), 7.10 (m, 3H); MS (ESI(+)) m/e 256.0 (M+H)⁺.

Example 100DN-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 100C and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 3.97 (s, 3H), 5.21 (s, 2H), 7.05 (d, J=8.14 Hz, 1H), 7.17 (d,J=8.14 Hz, 1H), 7.41 (d, J=8.82 Hz, 3H), 7.45-7.56 (m, 1H), 7.61 (d,J=8.48 Hz, 2H), 8.64 (dd, J=7.12, 2.37 Hz, 1H), 8.96 (d, J=2.71 Hz, 1H),9.34 (s, 1H); MS (ESI(+)) m/e 461 (M+H)⁺.

Example 101N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 100C and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H), 3.96 (s, 3H), 5.21 (s, 2H), 6.80 (d, J=7.46 Hz,1H), 7.04 (d, J=8.14 Hz, 1H), 7.10-7.35 (m, 4H), 7.37 (d, J=8.48 Hz,2H), 7.59 (d, J=8.82 Hz, 2H), 8.64 (s, 1H), 8.81 (s, 1H); MS (ESI(+))m/e 389 (M+H)⁺.

Example 102N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 100C and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 3.96 (s, 3H), 5.21 (s, 2H), 7.05 (d, J=7.80 Hz, 1H), 7.17 (d,J=8.14 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.53(t, J=7.80 Hz, 1H), 7.61 (m, 3H), 8.04 (s, 1H), 8.96 (s, 1H), 9.10 (s,1H); MS (ESI(+)) m/e 443.0 (M+H)⁺.

Example 103N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 100C and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 3.96 (s, 3H), 5.20 (s, 2H), 7.00-7.06 (m, 2H), 7.16 (d,J=8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.39 (d, J=8.81 Hz, 2H), 7.60 (d,J=8.48 Hz, 2H), 7.73 (t, J=2.03 Hz, 1H), 8.92 (s, 1H), 8.94 (s, 1H); MS(ESI(+)) m/e 409 (M+H)⁺.

Example 104N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 100C and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.28 (s, 3H), 3.96 (s, 3H), 5.21 (s, 2H), 6.75-6.90 (m, 1H),7.00-7.20 (m, 3H), 7.39 (d, J=8.81 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H),8.00 (dd, J=7.63, 1.86 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.22 (s, 1H);MS (ESI(+)) m/e 407.0 (M+H)⁺.

Example 105N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaExample 105A 4-iodo-7-(4-mompholinylmethyl)-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 15E for2-bromo-6-fluorobenzonitrile in Example 95A.

Example 105B4-(4-aminophenyl)-7-(4-morpholinylmethyl)-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 105A forExample 15F in Example 15G. ¹H NMR (300 MHz, DMSO-d₆) δ 2.38-2.45 (m,4H), 3.55-3.63 (m, 4H), 3.70 (s, 2H), 5.21 (s, 2H), 5.38 (s, 2H), 6.69(d, J=8.48 Hz, 2H), 7.02 (d, J=7.46 Hz, 1H), 7.15 (d, J=8.48 Hz, 2H),7.45 (d, J=7.46 Hz, 1H).

Example 105CN-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 105B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 7.13(d, J=7.46 Hz, 1H), 7.35-7.55 (m, 5H), 7.64 (d, J=8.81 Hz, 2H), 8.64(dd, J=7.29, 2.20 Hz, 1H), 8.99 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS(ESI(+)) m/e 530 (M+H)⁺.

Example 106N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 105B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,CF₃CO₂D) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 7.12(d, J=7.46 Hz, 1H), 7.33 (d, J=7.46 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H),7.50-7.68 (m, 5H), 8.04 (s, 1H), 9.04 (s, 1H), 9.16 (s, 1H); MS (ESI(+))m/e 512 (M+H)⁺.

Example 107N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 105B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.22 (s, 2H),6.95-7.06 (m, 1H), 7.12 (d, J=7.46 Hz, 1H), 7.25-7.38 (m, 2H), 7.44 (d,J=8.48 Hz, 2H), 7.52 (d, J=7.80 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H),7.70-7.78 (m, 1H), 8.99 (s, 2H); MS (ESI(+)) m/e 478 (M+H)⁺.

Example 108N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 105B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H), 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.23(s, 2H), 6.80 (d, J=7.80 Hz, 1H), 7.05-7.35 (m, 5H), 7.42 (d, J=8.48 Hz,1H), 7.52 (d, J=7.12 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H), 8.67 (s, 1H),8.86 (s, 1H); MS (ESI(+)) m/e 458 (M+H)⁺.

Example 109N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 105B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.28 (s, 3H), 2.35-2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.74 (s,2H), 5.23 (s, 2H), 6.75-6.85 (m, J=2.37 Hz, 1H), 7.05-7.18 (m, 2H), 7.44(d, J=8.48 Hz, 2H), 7.52 (d, J=7.80 Hz, 1H), 7.62 (d, J=8.48 Hz, 2H),8.00 (dd, J=7.80, 1.70 Hz, 1H), 8.55 (d, J=2.37 Hz, 1H), 9.25 (s, 1H);MS (ESI(+)) m/e 476 (M+H)⁺.

Example 110N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 105B and1-isocyanato-3,5-dimethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.24 (s, 6H), 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.23(s, 2H), 6.63 (s, 1H), 7.05-7.15 (m, 3H), 7.42 (d, J=8.48 Hz, 2H), 7.52(d, J=7.46 Hz, 1H), 7.61 (d, J=8.81 Hz, 2H), 8.59 (s, 1H), 8.84 (s, 1H);MS (ESI(+)) m/e 472 (M+H)⁺.

Example 111N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3-phenoxyphenyl)urea

The desired product was prepared by substituting Example 105B and1-isocyanato-3-phenoxybenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.40-2.48 (m, 4H), 3.55-3.64 (m, 4H), 3.73 (s, 2H), 5.21 (s,2H), 6.60-6.68 (m, 1H), 7.00-7.20 (m, 5H), 7.25-7.32 (m, 2H), 7.35-7.45(m, 4H), 7.51 (d, J=7.46 Hz, 1H), 7.59 (d, J=8.82 Hz, 2H), 8.84 (s, 1H),8.87 (s, 1H); MS (ESI(+)) m/e 536.1 (M+H)⁺.

Example 112N-{4-[3-amino-7-(4-morpholinylmethyl)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 105B and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.40-2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.73 (s, 2H), 5.22 (s,2H), 7.10-7.35 (m, 4H), 7.43 (d, J=8.48 Hz, 2H), 7.52 (d, J=7.46 Hz,1H), 7.62 (d, J=8.48 Hz, 2H), 7.88 (t, J=1.86 Hz, 1H), 8.96 (s, 2H); MS(ESI(+)) m/e 524 (M+H)⁺.

Example 113N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]ureaExample 113A 4-iodo-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 75A for2-bromo-6-fluorobenzonitrile in Example 95A.

Example 113B4-(4-aminophenyl)-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 113A forExample 15F in Example 15G. ¹H NMR (300 MHz, DMSO-d₆) δ 2.45-2.60 (m,4H), 2.76 (t, J=5.59 Hz, 2H), 3.50-3.70 (m, 4H), 4.28 (t, J=5.59 Hz,2H), 5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d, J=8.48 Hz, 2H), 6.92 (d,J=7.80 Hz, 1H), 7.05-7.18 (m, 3H); MS (ESI(+)) m/e 355.0 (M+H)⁺.

Example 113CN-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 113B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.45-2.60 (m, 4H), 2.78 (t, J=5.59 Hz, 2H), 3.50-3.65 (m,4H), 4.31 (t, J=5.59 Hz, 2H), 5.21 (s, 2H), 7.03 (d, J=8.14 Hz, 1H),7.19 (d, J=8.14 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.39 (d, J=8.81 Hz,2H), 7.53 (t, J=7.80 Hz, 1H), 7.57-7.66 (m, 3H), 8.04 (s, 1H), 8.96 (s,1H), 9.10 (s, 1H); MS (ESI(+)) m/e 542.1, 540.1.

Example 114N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 113B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.28 (s, 3H), 2.45-2.55 (m, 4H), 2.78 (t, J=5.59 Hz, 2H),3.50-3.65 (m, 4H), 4.31 (t, J=5.76 Hz, 2H), 5.21 (s, 2H), 6.75-6.84 (m,1H), 7.03 (d, J=8.14 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.19 (d,J=8.14 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.00(dd, J=7.80, 2.03 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.22 (s, 1H); MS(ESI(+)) m/e 506.1 (M+H)⁺.

Example 115N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 113B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.45-2.55 (m, 4H), 2.78 (t, J=5.26 Hz, 2H), 3.50-3.67 (m,4H), 4.31 (t, J=5.09 Hz, 2H), 5.21 (s, 2H), 7.03 (d, J=7.80 Hz, 1H),7.19 (d, J=7.80 Hz, 1H), 7.35-7.70 (m, 6H), 8.64 (dd, J=6.78, 1.36 Hz,1H), 8.96 (d, J=2.37 Hz, 1H), 9.34 (s, 1H); MS (ESI(+)) m/e 560.1(M+H)⁺.

Example 116N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1,2-benzisoxazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 113B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H), 2.45-2.55 (m, 4H), 2.78 (t, J=5.26 Hz, 2H),3.50-3.70 (m, 4H), 4.31 (t, J=4.92 Hz, 2H), 5.21 (s, 2H), 6.80 (d,J=7.46 Hz, 1H), 7.02 (d, J=7.80 Hz, 1H), 7.10-7.30 (m, 4H), 7.37 (d,J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H), 8.66 (s, 1H), 8.83 (s, 1H); MS(ESI(+)) m/e 488 (M+H)⁺.

Example 117N-{4-[3-amino-7-(2-methoxyethoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 68C and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The crudesuspension was filtered and the solid collected was washed withdichloromethane to provide the desired product. MS (ESI(+)) m/e 450(M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 3.36 (s, 3H), 3.76 (t,J=4.75 Hz, 2H), 4.26-4.29, (m, 2H), 4.29 (s, 2H), 6.68 (d, J=7.80 Hz,1H), 6.80 (d, J=7.80 Hz, 1H), 6.82 (m, 1H), 7.11 (dd, J=11.53, 8.14 Hz,1H), 7.36 (d, J=8.82 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80,2.03 Hz, 1H), 8.52 (d, J=2.37 Hz, 1H), 9.16 (s, 1H).

Example 118N-(4-{3-amino-7-[2-(4-morpholinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 75B and 1-fluoro-2-isocyanato-4-methylbenzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(+)) m/e 505 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s,3H), 2.73 (m, 2H), 3.71 (m, 6H), 4.04 (m, 2H), 4.53 (m, 2H), 6.74 (d,J=7.80 Hz, 1H), 6.81 (m, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.12 (dd,J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.82 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H),8.01 (s, 1H), 8.52 (d, J=2.71 Hz, 1H), 9.18 (s, 1H).

Example 119N-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)ureaExample 119A 2-fluoro-6-iodo-3-(methoxymethoxy)benzonitrile

A 0° C. solution of Example 68A (250 mg, 0.95 mmol) in THF (5 mL) atroom temperature was treated with NaH (25 mg, 95%, 1.05 mmol), stirredfor 5 minutes, treated with chloromethyl methyl ether (0.108 mL, 1.4mmol), stirred overnight, and partitioned between water and ethylacetate. The organic extract was washed with brine, dried (MgSO₄),filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel with 2% ethyl acetate/hexanes to provide0.21 g of the desired product. R_(f)=0.4 (10% ethyl acetate/hexanes).

Example 119BN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 119A and1-fluoro-2-isocyanato-4-methylbenzene for 2-fluoro-6-iodobenzonitrileand 1-isocyanato-3-methylbenzene, respectively, in Examples 1A-1C. MS(ESI(+)) m/e 436 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 3.46(s, 3H), 4.33 (s, 2H), 5.34 (s, 2H), 6.69 (d, J=7.80 Hz, 1H), 6.78-6.83(m, 1H), 6.92 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36(d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.01 (dd, J=7.80, 1.70 Hz,1H), 8.52 (d, J=2.71 Hz, 1H), 9.17 (s, 1H), 11.90 (s, 1H).

Example 120N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

A mixture of Example 119B (90 mg) and a 1:1:1 mixture of 3NHCl/methanol/THF (3 mL) was heated to 50° C. for 3 hours, concentratedto half its original volume, and partitioned between saturated NaHCO₃and ethyl acetate. The organic extract was dried (MgSO₄), filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel with 5% methanol/dichloromethane to provide 30 mg of thedesired product. MS (ESI(+)) m/e 392 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.28 (s, 3H), 4.25 (s, 2H), 6.60 (d, J=5.76 Hz, 2H), 6.82 (m, J=5.09,3.05 Hz, 1H), 7.11 (m, 2H), 7.33 (d, J=8.48 Hz, 1H), 7.54 (d, J=8.81 Hz,2H), 8.01 (dd, J=7.97, 2.20 Hz, 1H), 8.51 (d, J=2.71 Hz, 1H), 9.14 (s,1H), 9.84 (s, 1H), 11.58 (s, 1H).

Example 121N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)ureaExample 121A 4-(4-aminophenyl)-7-(methoxymethoxy)-1H-indazol-3-amine

The desired product was prepared by substituting Example 119A forExample 15E in Examples 15F-G. MS (ESI(+)) m/e 285 (M+H)⁺.

Example 121BN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 121A forExample 15G in Example 15H.

Example 121CN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 121B for Example 119B in Example 120, thenpurifying the resulting product by HPLC using the conditions describedin Example 15H. MS (ESI(+)) m/e 378 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ6.68-6.72 (m, 2H), 6.79 (td, J=8.34, 2.34 Hz, 1H), 7.14 (d, J=8.11 Hz,1H), 7.31 (m, 1H), 7.35 (d, J=8.42 Hz, 2H), 7.51 (dt, J=12.01, 2.26 Hz,1H), 7.56 (d, J=8.42 Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).

Example 122N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)ureaExample 122AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 121A and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.

Example 122BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 122A for Example 119B in Example 120 then purifyingthe resulting product by HPLC using the conditions described in Example15H. MS (ESI(+)) m/e 438 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 6.69-6.73(m, 2H), 7.16 (d, J=7.80 Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.32-7.34 (m,1H), 7.35 (d, J=8.42 Hz, 2H), 7.56 (d, J=8.73 Hz, 2H), 7.88 (t, J=1.87Hz, 1H), 8.90 (s, 1H), 8.95 (s, 1H).

Example 123N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-ethylphenyl)ureaExample 123AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 121A and1-ethyl-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.

Example 123BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 123A for Example 119B in Example 120 then purifyingthe resulting product by HPLC using the conditions described in Example15H. MS (ESI(+)) m/e 388 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.19 (t,J=7.49 Hz, 3H), 2.58 (q, J=7.49 Hz, 2H), 6.65-6.70 (m, 2H), 6.83 (d,J=7.49 Hz, 1H), 7.19 (t, J=7.80 Hz, 1H), 7.27 (d, J=8.11 Hz, 1H),7.33-7.34 (m, 3H), 7.55 (d, J=8.42 Hz, 2H), 8.64 (s, 1H), 8.74 (s, 1H).

Example 124N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaExample 124AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 121A and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.

Example 124BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 124A for Example 119B in Example 120 then purifyingthe resulting product by HPLC using the conditions described in Example15H. MS (ESI(+)) m/e 446 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 6.68-6.72(m, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.38-7.40 (m, 1H), 7.51 (m, 1H), 7.57(d, J=8.73 Hz, 2H), 8.64 (dd, J=7.17, 2.18 Hz, 1H), 8.93 (d, J=2.81 Hz,1H), 9.28 (s, 1H).

Example 125N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]ureaExample 125AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 121A and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.

Example 125BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 125A for Example 119B in Example 120 then purifyingthe resulting product by HPLC using the conditions described in Example15H. MS (ESI(−)) m/e 444 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 6.72-6.76(m, 2H), 7.36 (d, J=8.42 Hz, 2H), 7.44 (t, J=9.67 Hz, 1H), 7.58 (d,J=8.73 Hz, 2H), 7.65-7.68 (m, 1H), 8.03 (dd, J=6.39, 2.65 Hz, 1H), 9.02(s, 1H), 9.19 (s, 1H).

Example 126N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)ureaExample 126AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 121A and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.

Example 126BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 126A for Example 119B in Example 120 then purifyingthe resulting product by HPLC using the conditions described in Example15H. MS (ESI(−)) m/e 392 (M−H)⁻; ¹H NMR (500 MHz, DMSO-d₆) δ 6.69-6.73(m, 1H), 7.01-7.03 (m, 1H), 7.30-7.31 (m, 2H), 7.35 (d, J=8.73 Hz, 2H),7.56 (d, J=8.73 Hz, 2H), 7.74 (d, J=1.87 Hz, 1H), 8.91 (s, 1H), 8.98 (s,1H).

Example 127N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]ureaExample 127AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 121A and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.

Example 127BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 127A for Example 119B in Example 120 then purifyingthe resulting product by HPLC using the conditions described in Example15H. MS (ESI(+)) m/e 428 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 6.70-6.74(m, 2H), 7.32 (d, J=7.49 Hz, 1H), 7.36 (d, J=8.42 Hz, 2H), 7.52 (t,J=7.95 Hz, 1H), 7.58 (d, J=8.42 Hz, 2H), 7.60 (d, J=9.04 Hz, 1H), 8.04(s, 1H), 8.96 (s, 1H), 9.14 (s, 1H).

Example 128N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-phenylurea Example128AN-{4-[3-amino-7-(methoxymethoxy)-1H-indazol-4-yl]phenyl}-N′-phenylurea

The desired product was prepared by substituting Example 121A andisocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,respectively, in Example 15H.

Example 128BN-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-phenylurea

The desired product can be prepared by substituting Example 128A forExample 119B in Example 120. MS (ESI(−)) m/e 358 (M−H)⁻; ¹H NMR (300MHz, DMSO-d₆) δ 6.57-6.64 (m, 2H), 6.97 (t, J=7.29 Hz, 1H), 7.29 (t,J=8.13 Hz, 2H), 7.32 (d, J=8.82 Hz, 2H), 7.47 (d, J=7.46 Hz, 2H), 7.54(d, J=8.82 Hz, 2H), 8.71 (s, 1H), 8.77 (s, 1H).

Example 129N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylureaExample 129A4-(4-aminophenyl)-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-3-amine

The desired product was prepared by substituting2-(1-pyrrolidinyl)ethanol for 2-(4-morpholinyl)ethanol in Examples 75Aand 75B. MS (ESI(+)) m/e 338 (M+H)⁺.

Example 129BN-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylurea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A and isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 457 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.93 (br s, 2H), 2.08 (br s,2H), 3.25 (br s, 4H), 3.68 (br s, 2H), 4.46 (t, J=4.80 Hz, 2H), 6.74 (d,J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.33 Hz, 1H), 7.29(t, J=7.80 Hz, 2H), 7.36 (d, J=8.73 Hz, 2H), 7.47 (d, J=7.49 Hz, 2H),7.58 (d, J=8.42 Hz, 2H), 8.74 (s, 1H), 8.82 (s, 1H).

Example 130N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A for Example 15G in Example 15H. MS (ESI(+))m/e 475 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.92 (br s, 2H), 2.07 (br s,2H), 3.24 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.75 (d,J=7.49 Hz, 1H), 6.79 (td, J=8.50, 2.34 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H),7.15 (dd, J=8.11, 1.25 Hz, 1H), 7.29-7.34 (m, 1H), 7.37 (d, J=8.73 Hz,2H), 7.52 (dt, J=12.01, 2.26 Hz, 1H), 7.58 (d, J=8.73 Hz, 2H), 9.00 (s,1H), 9.08 (s, 1H).

Example 131N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A and 1-fluoro-2-isocyanato-4-methylbenzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(+)) m/e 489 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.93 (br s,2H), 2.07 (br s, 2H), 2.28 (s, 3H), 3.25 (br s, 2H), 3.69 (br s, 4H),4.47 (t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.80-6.82 (m, 1H),6.88 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.38, 8.26 Hz, 1H), 7.37 (d,J=8.42 Hz, 2H), 7.58 (d, J=8.73 Hz, 2H), 7.99 (dd, J=7.80, 1.56 Hz, 1H),8.53 (d, J=2.49 Hz, 1H), 9.20 (s, 1H).

Example 132N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 129A and 1-isocyanato-3-methylbenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 471 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.93 (br s, 2H),2.07 (br s, 2H), 2.29 (s, 3H), 3.25 (br s, 2H), 3.69 (br s, 4H), 4.48(t, J=4.80 Hz, 2H), 6.77 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.49 Hz, 1H),6.90 (d, J=7.80 Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.11 Hz,1H), 7.33 (s, 1H), 7.36 (d, J=8.73 Hz, 2H), 7.59 (d, J=8.73 Hz, 2H),8.79 (s, 1H), 8.95 (s, 1H).

Example 133N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-bromophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A and 1-bromo-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 535 and 537 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.93 (br s,2H), 2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15 (d,J=8.11 Hz, 1H), 7.25 (t, J=8.11 Hz, 1H), 7.34 (d, J=9.36 Hz, 1H), 7.37(d, J=8.42 Hz, 2H), 7.59 (d, J=8.42 Hz, 2H), 7.89 (t, J=1.87 Hz, 1H),9.06 (s, 1H), 9.10 (s, 1H).

Example 134N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 543 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.93 (br s, 2H), 2.08 (br s,2H), 3.25 (br s, 2H), 3.69 (br s, 4H), 4.47 (t, J=4.80 Hz, 2H), 6.74 (d,J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.39 (d, J=8.42 Hz, 2H), 7.41(m, 1H), 7.51 (t, J=9.67 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 8.64 (dd,J=7.33, 2.34 Hz, 1H), 8.94 (d, J=2.49 Hz, 1H), 9.30 (s, 1H).

Example 135N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 491 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.93 (br s, 2H),2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br s, 4H), 4.47 (t, J=4.80 Hz,2H), 6.76 (d, J=7.49 Hz, 1H), 6.90 (d, J=7.80 Hz, 1H), 7.02 (m, 1H),7.31 (d, J=5.30 Hz, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.59 (d, J=8.73 Hz,2H), 7.74 (s, 1H), 9.10 (s, 1H), 9.15 (s, 1H).

Example 136N-(4-{3-amino-7-[2-(1-pyrrolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 129A and 1-isocyanato-3-(trifluoromethyl)benzenefor Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, inExample 15H. MS (ESI(+)) m/e 525 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ1.93 (br s, 2H), 2.07 (br s, 2H), 3.25 (br s, 2H), 3.68 (br s, 4H), 4.47(t, J=4.80 Hz, 2H), 6.74 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H),7.32 (d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.80 Hz,1H), 7.60 (d, J=8.42 Hz, 2H), 7.60 (d, J=6.55 Hz, 1H), 8.05 (s, 1H),9.10 (s, 1H), 9.28 (s, 1H).

Example 137N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylureaExample 137A4-(4-aminophenyl)-7-[2-(diethylamino)ethoxy]-1H-indazol-3-amine

The desired product was prepared by substituting 2-(diethylamino)ethanolfor 2-(4-morpholinyl)ethanol in Examples 75A and 75B. MS (ESI(+)) m/e340 (M+H)⁺.

Example 137BN-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylurea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 137A and isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 459 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t, J=7.17 Hz, 6H),3.33 (br s, 4H), 3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.74 (d,J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 6.98 (t, J=7.49 Hz, 1H), 7.29(t, J=7.95 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 7.48 (d, J=7.80 Hz, 2H),7.58 (d, J=8.73 Hz, 2H), 8.83 (s, 1H), 8.91 (s, 1H).

Example 138N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate salt) bysubstituting Example 137A for Example 15G in Example 15H. MS (ESI(+))m/e 477 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t, J=7.33 Hz, 6H),3.34 (br s, 4H), 3.60 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.76 (d,J=7.80 Hz, 1H), 6.79 (t, J=8.58 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.15(d, J=8.11 Hz, 1H), 7.31 (q, J=7.61 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H),7.52 (dt, J=11.93, 2.14 Hz, 1H), 7.59 (d, J=8.42 Hz, 2H), 9.02 (s, 1H),9.11 (s, 1H).

Example 139N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate salt) bysubstituting Example 137A and 1-fluoro-2-isocyanato-4-methylbenzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI(+)) m/e 491 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t,J=7.33 Hz, 6H), 2.28 (s, 3H), 3.33 (br d, J=8.42 Hz, 4H), 3.62 (br s,2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.80-6.82 (m,1H), 6.89 (d, J=7.80 Hz, 1H), 7.11 (dd, J=11.38, 8.26 Hz, 1H), 7.37 (d,J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 7.99 (dd, J=7.95, 1.72 Hz, 1H),8.54 (d, J=2.50 Hz, 1H), 9.22 (s, 1H).

Example 140N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate salt) bysubstituting Example 137A and 1-isocyanato-3-methylbenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 473 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t, J=7.33 Hz,6H), 2.29 (s, 3H), 3.34 (br s, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz,2H), 6.74 (d, J=7.49 Hz, 1H), 6.80 (d, J=7.17 Hz, 1H), 6.88 (d, J=7.80Hz, 1H), 7.16 (t, J=7.80 Hz, 1H), 7.26 (d, J=8.11 Hz, 1H), 7.32 (s, 1H),7.35 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H), 8.72 (s, 1H), 8.87 (s,1H).

Example 141N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-bromophenyl)urea

The desired product was prepared as the bis(trifluoroacetate salt) bysubstituting Example 137A and 1-bromo-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 537 and 539 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t,J=7.33 Hz, 6H), 3.30-3.35 (m, 4H), 3.61 (br s, 2H), 4.49 (t, J=4.80 Hz,2H), 6.75 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.16 (d, J=7.80Hz, 1H), 7.25 (t, J=7.95 Hz, 1H), 7.33-7.35 (m, 1H), 7.36 (d, J=8.42 Hz,2H), 7.59 (d, J=8.42 Hz, 2H), 7.89 (m, 1H), 9.05 (s, 1H), 9.09 (s, 1H).

Example 142N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 137A and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 545 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t, J=7.17 Hz, 6H),3.33 (br s, 4H), 3.62 (br s, 2H), 4.50 (t, J=4.80 Hz, 2H), 6.77 (d,J=7.80 Hz, 1H), 6.89 (d, J=7.80 Hz, 1H), 7.39 (m, J=8.42 Hz, 3H), 7.51(t, J=9.85 Hz 1H), 7.60 (d, J=8.73 Hz, 2H), 8.64 (dd, J=7.17, 2.18 Hz,1H), 8.97 (d, J=2.81 Hz, 1H), 9.35 (s, 1H).

Example 143N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 137A and 1-chloro-3-isocyanatobenzene for Example15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)) m/e 493 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 1.27 (t, J=7.17 Hz,6H), 3.34 (br s, 4H), 3.62 (br s, 2H), 4.49 (t, J=4.80 Hz, 2H), 6.75 (d,J=7.80 Hz, 1H), 6.88 (d, J=7.80 Hz, 1H), 7.02 (td, J=4.37, 2.18 Hz, 1H),7.30-7.31 (m, 2H), 7.37 (d, J=8.42 Hz, 2H), 7.58 (d, J=8.42 Hz, 2H),7.74 (s, 1H), 9.01 (s, 1H), 9.06 (s, 1H).

Example 144N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 137A and 1-isocyanato-3-(trifluoromethyl)benzenefor Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, inExample 15H. MS (ESI(+)) m/e 527 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ1.27 (t, J=7.33 Hz, 6H), 3.32-3.34 (br s, 4H), 3.61 (br s, 2H), 4.49 (t,J=4.80 Hz, 2H), 6.75 (d, J=7.80 Hz, 1H), 6.88 (d, J=7.49 Hz, 1H), 7.31(d, J=7.80 Hz, 1H), 7.37 (d, J=8.42 Hz, 2H), 7.52 (t, J=7.95 Hz, 1H),7.60-7.61 (m, 3H), 8.05 (s, 1H), 9.12 (s, 1H), 9.30 (s, 1H).

Example 145N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)ureaExample 145A3-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)-1,5,5-trimethyl-2,4-imidazolidinedione

The desired product was prepared by substituting3-(2-hydroxyethyl)-1,5,5-trimethyl-2,4-imidazolidinedione for2-(4-morpholinyl)ethanol in Examples 75A and 75B. ¹H NMR (300 MHz,DMSO-d₆) δ 1.27 (s, 6H), 2.80 (s, 3H), 3.81 (t, J=6.27 Hz, 2H), 4.32 (t,J=6.27 Hz, 2H), 5.19 (s, 2H), 6.57 (d, J=7.80 Hz, 1H), 6.65 (d, J=8.14Hz, 2H), 6.76 (d, J=7.80 Hz, 1H), 7.07 (d, J=8.14 Hz, 2H), 11.59 (s,1H); MS (ESI(+)) m/e 409 (M+H)⁺.

Example 145BN-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 145A and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting producty by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆)δ 1.27 (s, 6H), 2.29 (s, 3H), 2.81 (s, 3H), 3.83 (t, J=5.93 Hz, 2H),4.35 (t, J=5.93 Hz, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.81 (t, J=7.46 Hz,2H), 7.05-7.45 (m, 5H), 7.56 (d, J=8.48 Hz, 2H), 8.62 (s, 1H), 8.75 (s,1H), 11.75 (s, 1H); MS (ESI(+)) m/e 542 (M+H)⁺.

Example 146N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 145A and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-d₆) δ 1.27 (s, 6H), 2.81 (s, 3H), 3.83 (t, J=6.27 Hz, 2H),4.35 (t, J=6.44 Hz, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz,1H), 6.95-7.06 (m, 1H), 7.25-7.40 (m, 4H), 7.56 (d, J=8.81 Hz, 2H), 7.73(s, 1H), 8.86 (s, 1H), 8.93 (s, 1H), 11.74 (s, 1H); MS (ESI(+)) m/e 562(M+H)⁺.

Example 147N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 145A and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H thenpurifying the resulting producty by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane. ¹H NMR (300 MHz, DMSO-d₆)δ 1.27 (s, 6H), 2.28 (s, 3H), 2.81 (s, 3H), 3.83 (t, J=6.27 Hz, 2H),4.35 (t, J=6.27 Hz, 2H), 6.67 (d, J=7.80 Hz, 1H), 6.70-6.90 (m, 2H),7.11 (dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.48 Hz, 2H), 7.56 (d,J=8.48 Hz, 2H), 7.90-8.10 (dd, J=7.97, 1.86 Hz, 1H), 8.52 (d, J=2.71 Hz,1H), 9.17 (s, 1H), 11.72 (s, 1H); MS (ESI(+)) m/e 560 (M+H)⁺.

Example 148N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 145A and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-d₆) δ 1.27 (s, 6H), 2.81 (s, 3H), 3.83 (t, J=6.27 Hz, 2H),4.35 (t, J=6.44 Hz, 2H), 6.68 (d, J=7.80 Hz, 1H), 6.82 (d, J=8.14 Hz,1H), 7.25-7.45 (m, 3H), 7.45-7.65 (m, 4H), 8.04 (s, 1H), 8.90 (s, 1H),9.09 (s, 1H), 11.73 (s, 1H); MS (ESI(+)) m/e 596 (M+H)⁺.

Example 149N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 149A N-(4-bromo-2-ethylphenyl)-N′-(2-fluoro-5-methylphenyl)urea

A solution of 4-bromo-2-ethylaniline (200 mg) in dichloromethane (10 mL)was treated with 1-fluoro-2-isocyanato-4-methylbenzene (151 mg), stirredat room temperature overnight, diluted with hexanes, and filtered. Thefilter cake provided 227 mg of the desired product. MS (ESI(+)) m/e351,353 (M+H)⁺.

Example 149BN-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

A mixture of Example 149A (219 mg, 0.62 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (190 mg, 0.75mmol), potassium acetate (183 mg), and PdCl₂(dppf).CH₂Cl₂ (15 mg) in DMF(6 mL) was degassed then heated to 80° C. for 2 hours. The mixture wasused directly in the next reaction.

Example 149CN-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 149B andPdCl₂(dppf)-CH₂Cl₂ for Example 1B and Pd(PPh₃)₄, respectively, inExample 1C. Additionally, DMF was used in place of DME. ¹H NMR (300 MHz,DMSO-d₆) δ 1.24 (t, J=7.46 Hz, 3H), 2.28 (s, 3H), 2.71 (q, J=7.46 Hz,2H), 4.35 (s, 2H), 6.75-6.85 (m, 2H), 7.12 (dd, J=11.53, 8.14 Hz, 1H),7.25-7.35 (m, 4H), 7.99 (d, J=8.14 Hz, 1H), 8.06 (dd, J=7.80, 2.03 Hz,1H), 8.44 (s, 1H), 8.99 (d, J=2.03 Hz, 1H), 11.71 (s, 1H); MS (ESI(+))m/e 404 (M+H)⁺.

Example 150N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-(trifluoromethyl)benzene for1-fluoro-2-isocyanato-4-methylbenzene in Examples 149A-C. ¹H NMR (300MHz, DMSO-d₆) δ 1.24 (t, J=7.46 Hz, 3H), 2.71 (q, J=7.69 Hz, 2H), 4.35(s, 2H), 6.75-6.90 (m, 1H), 7.20-7.40 (m, 4H), 7.45-7.60 (m, 3H), 7.94(d, J=8.14 Hz, 1H), 8.07 (s, 1H), 8.13 (s, 1H), 9.43 (s, 1H), 11.72 (s,1H); MS (ESI(+)) m/e 440 (M+H)⁺.

Example 151N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 1-fluoro-2-isocyanato-4-methylbenzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. ¹H NMR (400 MHz, DMSO-d₆) δ 2.27 (s, 3H), 6.74-6.83 (m, 2H), 7.13(m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.58 (d, J=8.59 Hz, 2H), 7.99 (d,J=6.44 Hz, 1H), 8.52 (d, J=2.45 Hz, 1H), 9.21 (s, 1H); MS (ESI(+)) m/e394 (M+H)⁺.

Example 152N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)ureaExample 152A 2,3-difluoro-4-(hydroxymethyl)-6-iodobenzonitrile

A −78° C. solution of Example 26A (5.0 g, 18.9 mmol) in THF was treatedwith LDA (2M in hexanes, 11.5 mL, 22.6 mmol), stirred for 1 hour at −78°C., treated with methyl formate (2.34 mL, 37.8 mmol), stirred at −78° C.for 30 minutes, warmed to 0° C. for 1 hour, quenched with saturatedNH₄Cl and extracted three times with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄), filtered, andconcentrated. The residue was immediately dissolved in ethanol (100 mL),cooled to 0° C., and treated portionwise with NaBH₄ (1.08 g). Thereaction was stirred at 0° C. for 2 hours, quenched with acetone,stirred for 5 minutes, poured into water, and extracted three times withethyl acetate. The combined extracts were washed with brine, dried(MgSO₄), filtered, and concentrated. The residue was purified by flashcolumn chromatography on silica gel with 2:1 hexanes/ethyl acetate togive 1.02 g of the desired product. R_(f)=0.84 (ethyl acetate).

Example 152B (3-amino-7-fluoro-4-iodo-1H-indazol-6-yl)methanol

The desired product was prepared by substituting Example 152A for2-fluoro-6-iodobenzonitrile in Example 1A. R_(f)=0.53 (ethyl acetate).

Example 152CN-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

A mixture of Example 152B (50 mg, 0.16 mmol), Example 5A (66 mg, 0.18mmol), Pd(PPh₃)₄ (9 mg, 0.008 mmol), and Na₂CO₃ (43 mg, 0.4 mmol) intoluene (2 mL), ethanol (1 mL), and water (1 mL) was degassed and heatedat 140° C. for 8 minutes with stirring using a Smith Synthesizer in asepta capped 5 mL process vial at 300 W. The samples were cooled using40 psi pressurized air. The mixture was concentrated and the residue waspurified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100mm, 7 μm particle size) using a gradient of 10% to 100%acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at aflow rate of 40 mL/min to provide 26 mg of the desired product as thetrifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 4.65(d, J=1.36 Hz, 2H), 6.81 (m, 1H), 6.86 (d, J=5.76 Hz, 1H), 7.11 (dd,J=11.36, 8.31 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H),8.01 (dd, J=7.80, 2.03 Hz, 1H), 8.53 (d, J=2.37 Hz, 1H), 9.21 (s, 1H);MS (ESI(+)) m/e 424 (M+H)⁺.

Example 153N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 98A for Example 5A in Example 152C. ¹H NMR (300MHz, DMSO-d₆) δ 4.65 (d, J=1.70 Hz, 2H), 6.87 (d, J=5.76 Hz, 1H), 7.32(d, J=7.46 Hz, 1H), 7.39 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H),7.58-7.64 (m, 3H), 8.04 (s, 1H), 8.99 (s, 1H), 9.14 (s, 1H); MS (ESI(+))m/e 460 (M+H)⁺; Anal. calcd. for C₂₂H₁₇F₄N₅O₂.1.0CF₃CO₂H: C, 50.27; H,3.15; N, 12.21;

Found: C, 50.15; H, 3.15; N, 12.41.

Example 154N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstitutingN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 152C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.65 (d,J=1.36 Hz, 2H), 6.86 (d, J=5.76 Hz, 1H), 7.03 (td, J=4.41, 2.03 Hz, 1H),7.27-7.36 (m, 2H), 7.39 (d, J=8.48 Hz, 2H), 7.60 (d, J=8.48 Hz, 2H),7.74 (m, 1H), 8.93 (s, 1H), 8.96 (s, 1H); MS (ESI(+)) m/e 426 (M+H)⁺.

Example 155N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 1B for Example 5A in Example 152C. ¹H NMR (300 MHz,DMSO-d₆) δ 2.29 (s, 3H), 4.65 (d, J=1.36 Hz, 2H), 6.80 (d, J=7.46 Hz,1H), 6.84 (d, J=5.76 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25 (d, J=7.80Hz, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.59 (d, J=8.48 Hz, 2H),8.64 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 406 (M+H)⁺.

Example 156N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstitutingN-(3-fluorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 152C. ¹H NMR (300 MHz, DMSO-d₆) δ 4.65 (d,J=1.02 Hz, 2H), 6.80 (td, J=8.65, 2.71 Hz, 1H), 6.84 (d, J=5.76 Hz, 1H),7.14 (d, J=9.16 Hz, 1H), 7.32 (m, 1H), 7.38 (d, J=8.48 Hz, 2H), 7.51(dt, J=11.87, 2.20 Hz, 1H), 7.59 (d, J=8.48 Hz, 2H), 12.13 (s, 1H); MS(ESI(+)) m/e 410 (M+H)⁺.

Example 157N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 157A 4-[(diethylamino)methyl]-2,3-difluoro-6-iodobenzonitrile

A 0° C. solution of Example 152A (350 mg, 1.18 mmol) in dichloromethane(10 mL) was treated with triethylamine (0.25 mL, 1.78 mmol) andmethanesulfonyl chloride (0.1 mL, 1.3 mmol), stirred at 0° C. for 1hour, treated with diethylamine (0.245 mL, 2.37 mmol), and overnight atroom temperature. The mixture was partitioned between 1N NaOH anddichloromethane and the organic extract was dried (MgSO₄), filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel with 3:1 hexanes/ethyl acetate to provide 0.263 g of thedesired product. MS (ESI(+)) 351 (M+H)⁺.

Example 157B 6-[(diethylamino)methyl]-7-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting Example 157A for2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) 363 (M+H)⁺.

Example 157CN-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 157B for Example 152B in Example 152C. ¹H NMR (300MHz, DMSO-d₆) δ 1.27 (t, J=7.29 Hz, 6H), 2.28 (s, 3H), 3.18 (m, 4H),4.48 (d, J=4.75 Hz, 2H), 6.82 (ddd, J=7.71, 5.17, 2.03 Hz, 1H), 6.94 (d,J=5.76 Hz, 1H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.44 (d, J=8.48 Hz,2H), 7.63 (d, J=8.82 Hz, 2H), 7.99 (dd, J=7.97, 1.87 Hz, 1H), 8.56 (d,J=2.71 Hz, 1H), 9.27 (s, 1H), 9.36 (br s, 1H); MS (ESI(+) 477 (M+H)⁺.

Example 158N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 157B and Example 98A for Example 152B and Example5A, respectively, in Example 152C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (t,J=7.29 Hz, 6H), 3.18 (m, 4H), 4.48 (d, J=4.75 Hz, 2H), 6.94 (d, J=5.76Hz, 1H), 7.33 (d, J=7.80 Hz, 1H), 7.44 (d, J=8.48 Hz, 2H), 7.53 (t,J=7.80 Hz, 1H), 7.60 (m, 1H), 7.65 (d, J=8.48 Hz, 2H), 8.06 (s, 1H),9.14 (s, 1H), 9.27 (s, 1H), 9.34 (br s, 1H); MS (ESI(+)) m/e 515 (M+H)⁺.

Example 159N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 157B andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 152B and Example 5A, respectively, in Example 152C. ¹H NMR(300 MHz, DMSO-d₆) δ 1.27 (t, J=7.29 Hz, 6H), 3.19 (m, 4H), 4.48 (d,J=4.75 Hz, 2H), 6.94 (d, J=5.76 Hz, 1H), 7.03 (dt, J=6.44, 2.20 Hz, 1H),7.27-7.37 (m, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.63 (d, J=8.48 Hz, 2H),7.75 (m, 1H), 9.06 (s, 1H), 9.32 (br s, 1H); MS (ESI(+)) m/e 481 (M+H)⁺.

Example 160N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 157B and Example 1B for Example 152B and Example5A, respectively, in Example 152C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (t,J=7.12 Hz, 6H), 2.29 (s, 3H), 3.18 (m, 4H), 4.48 (d, J=4.75 Hz, 2H),6.81 (d, J=7.12 Hz, 1H), 6.94 (d, J=5.76 Hz, 1H), 7.17 (t, J=7.80 Hz,1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.42 (d, J=8.48 Hz, 2H), 7.63 (d,J=8.48 Hz, 2H), 8.74 (s, 1H), 8.93 (s, 1H), 9.34 (br s, 1H); MS (ESI(+))m/e 461 (M+H)⁺.

Example 161N-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]ureaExample 161A 4-iodo-7-[(3-pyridinyloxy)methyl]-1H-indazol-3-amine

The desired product was prepared by substituting 3-pyridinol formorpholine in Examples 15E-F.

Example 161BN-(4-{3-amino-7-[(3-pyridinyloxy)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 161A andExample 98A for Example 152B and Example 5A, respectively, in Example152C then purifying the resulting producty by flash columnchromatography on silica gel with 5-8% methanol/dichloromethane. ¹H NMR(500 MHz, DMSO-d₆) δ 4.38 (s, 2H), 5.40 (s, 2H), 7.32 (d, J=7.17 Hz,1H), 7.34-7.38 (m, 2H), 7.42 (d, J=8.42 Hz, 2H), 7.52 (dd, J=15.59, 7.80Hz, 2H), 7.58-7.64 (m, 4H), 8.04 (s, 1H), 8.19 (d, J=4.68 Hz, 1H), 8.39(d, J=2.50 Hz, 1H), 8.96 (s, 1H), 9.12 (s, 1H), 11.92 (s, 1H); MS(ESI(+)) m/e 519 (M+H)⁺.

Example 162N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 162A 2-(4-iodo-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione

A mixture of Example 1A (1.09 g) and phthalic anhydride (0.75 g) indioxane (15 mL) was stirred overnight at 120° C. and concentrated. Theresidue was triturated from diethyl ether (15 mL) to provide 0.51 g ofthe desired product. MS (ESI(+)) m/e 388 (M+H)⁺.

Example 162B2-{4-iodo-1-[2-(4-morpholinyl)ethyl]-1H-indazol-3-yl}-1H-isoindole-1,3(2H)-dione

A mixture of Example 162A (100 mg), 4-(2-chloroethyl)morpholine (48 mg),and Na₂CO₃ (82 mg) in DMF (5 mL) was heated overnight at 80° C., cooledto room temperature, and partitioned between 1N HCl and ethyl acetate.The aqueous layer was basified with 1N KOH and extracted with ethylacetate. The extract was dried (MgSO₄), filtered, and concentrated toprovide 45 mg of the desired product. MS (ESI(+)) m/e 503 (M+H)⁺.

Example 162C 4-iodo-1-[2-(4-morpholinyl)ethyl]-1H-indazol-3-amine

A mixture of hydrazine hydrate (0.058 mL) and Example 162B (120 mg, 0.24mmol) in ethanol (5 mL) was stirred at 0° C. for 3 hours andconcentrated. The residue was purified by flash column chromatography onsilica gel with 5-8% methanol/dichloromethane to provide 95 mg of thedesired product.

Example 162DN-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 162C for Example 152B in Example 152C. MS (ESI(+))m/e 489 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 2.45 (d,J=4.07 Hz, 4H), 2.68 (t, J=6.61 Hz, 2H), 3.54 (t, J=4.05 Hz, 4H), 4.26(t, J=6.44 Hz, 2H), 4.41 (s, 2H), 6.78-6.83 (d, J=6.78 Hz, 2H), 7.11(dd, J=11.36, 8.31 Hz, 1H), 7.31 (t, J=8.48 Hz, 1H), 7.36-7.41 (m, 3H),7.59 (d, J=8.48 Hz, 2H), 8.01 (d, J=7.46 Hz, 1H), 8.54 (s, 1H), 9.21 (s,1H).

Example 163N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting 162C for Example 15F in Examples 15G-H. MS (ESI(+)) m/e 475(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.58 (t, J=5.77 Hz, 2H), 3.32-3.83(br m, 8H), 4.55 (t, J=6.24 Hz, 2H), 6.79 (td, J=8.42, 1.87 Hz, 1H),6.88 (d, J=6.55 Hz, 1H), 7.15 (dd, J=8.26, 1.09 Hz, 1H), 7.29-7.34 (m,1H), 7.38-7.42 (m, J=8.11, 8.11 Hz, 3H), 7.48 (d, J=8.11 Hz, 1H), 7.52(dt, J=11.85, 2.18 Hz, 1H), 7.62 (d, J=8.73 Hz, 2H), 9.06 (s, 1H), 9.12(s, 1H).

Example 164N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 162C and 1-chloro-3-isocyanatobenzene for Example15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H.MS (ESI(+)) m/e 491 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 3.58 (t, J=5.92Hz, 2H), 3.38-3.92 (br m, 8H), 4.55 (t, J=6.39 Hz, 2H), 6.88 (d, J=6.86Hz, 1H), 7.02-7.04 (m, 1H), 7.31-7.32 (m, 2H), 7.38-7.41 (m, J=7.95,7.95 Hz, 3H), 7.48 (d, J=8.11 Hz, 1H), 7.62 (d, J=8.73 Hz, 2H), 7.74 (s,1H), 9.09 (s, 1H), 9.11 (s, 1H).

Example 165N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 162C and 1-isocyanato-3-(trifluoromethyl)benzenefor Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, inExamples 15G-H. MS (ESI(+)) m/e 525 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ3.32-3.83 (br m, 8H), 3.58 (t, J=5.77 Hz, 2H), 4.55 (t, J=6.39 Hz, 2H),6.88 (d, J=7.17 Hz, 1H), 7.32 (d, J=7.80 Hz, 1H), 7.39-7.42 (m, 3H),7.48 (d, J=8.42 Hz, 1H), 7.53 (t, J=7.95 Hz, 1H), 7.61 (d, J=8.73 Hz,1H), 7.64 (d, J=8.73 Hz, 2H), 8.05 (s, 1H), 9.15 (s, 1H), 9.29 (s, 1H).

Example 166N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 162C and 1-isocyanato-3-methylbenzene for Example15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H.MS (ESI(+)) m/e 471 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 2.29 (s, 3H),3.58 (t, J=5.77 Hz, 2H), 3.39-3.88 (br m, 8H), 4.55 (t, J=6.39 Hz, 2H),6.80 (d, J=7.49 Hz, 1H), 6.87 (d, J=6.86 Hz, 1H), 7.17 (t, J=7.80 Hz,1H), 7.26 (d, J=8.42 Hz, 1H), 7.32 (s, 1H), 7.37-7.41 (m, 3H), 7.48 (d,J=8.11 Hz, 1H), 7.61 (d, J=8.42 Hz, 2H), 8.75 (s, 1H), 8.93 (s, 1H).

Example 167-I and 167-IIN-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaandN-[4-(3-amino-4-bromo-1H-indazol-6-yl)phenyl]-N′-(3-methylphenyl)ureaExample 167A 2,4-dibromo-6-fluorobenzonitrile

The desired product was prepared by substituting2,4-dibromo-6-fluorobenzoic acid (prepared as described in TetrahedronLett. 1996, 37, 6551-6554) for Example 15A in Examples 15B and 15C.

Example 167B 4,6-dibromo-1H-indazol-3-amine

The desired product was prepared by substituting Example 167A for2-fluoro-6-iodobenzonitrile in Example 1A. ¹H NMR (DMSO-d₆) δ 11.99 (1H,br s), 7.48 (1H, d, J=1.6 Hz), 7.24 (1H, s), 5.22 (1H, d, J=8.0 Hz).

Example 167-I and 167-IIN-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaandN-[4-(3-amino-4-bromo-1H-indazol-6-yl)phenyl]-N′-(3-methylphenyl)urea

A mixture of Example 167B (0.060 g, 0.021 mmol), Example 1B (0.073 g,0.21 mmol), Na₂CO₃ (0.052 g, 0.49 mmol), and Pd(PPh₃)₄ (0.014 g, 0.012mmol) in 2:1 DME/water (1.2 mL) was heated to 85° C. in a sealed tubeovernight. The reaction was treated with additional Pd(PPh₃)₄ (0.028 g,0.024 mmol), heated for two days, treated with additional catalyst(0.028 g, 0.024 mmol), heated to 160° C. for 2 hours, and cooled to roomtemperature. The mixture was diluted with ethyl acetate anddichloromethane, filtered, and concentrated. The concentrate waspurified by flash column chromatography on silica gel withmethanol/dichloromethane (2:100 to 5:100), then purified by preparativeHPLC with 30-100% CH₃CN/5 mM ammonium acetate buffer over 9 minutes toprovide the desired products.

Example 167-I

LC/MS 434.2 (M−H)⁻, LC retention time 3.00 min. ¹H NMR (DMSO-d₆) δ 7.508(2H, d, J=8.4 Hz), 7.454 (1H, d, J=1.2 Hz), 7.407 (2H, d, J=8.4 Hz),7.325 (1H, s), 7.257 (1H, d, J=6.0 Hz), 7.166 (1H, m), 6.888 (1H, s),6.799 (1H, d, J=7.6 Hz), 4.397 (2H, s), 2.328 (3H, s).

Example 167-II

LC/MS 434.0 (M−H)⁻, LC retention time 2.87 min. ¹H NMR (DMSO-d₆) δ 11.88(1H, br s), 8.961 (1H, br s), 8.782 (1H, br s), 7.637 (2H, d, J=8.8 Hz),7.560 (1H, d, J=8.8 Hz), 7.414 (2H, d, J=1.2 Hz), 7.352 (1H, d, J=1.2Hz), 7.319 (1H, s), 7.252 (1H, d, J=7.6 Hz), 7.181-7.142 (1H, m), 6.796(1H, d, J=7.6 Hz), 5.147 (2H, d, J=9.2 Hz), 2.285 (3H, s).

Example 168N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting N-(2-chloroethyl)-N,N-dimethylamine for4-(2-chloroethyl)morpholine in Example 162. MS (ESI(+)) m/e 447 (M+H)⁺;¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H), 2.87 (s, 3H), 2.88 (s, 3H),3.54 (q, J=5.65 Hz, 2H), 4.52 (t, J=6.10 Hz, 2H), 6.79-6.84 (m, 1H),6.88 (d, J=6.10 Hz, 1H), 7.12 (dd, J=11.36, 8.31 Hz, 1H), 7.37-7.42 (m,3H), 7.50 (d, J=7.79 Hz, 2H), 7.61 (d, J=8.48 Hz, 2H), 7.99 (dd, J=8.14,2.03 Hz, 1H), 8.55 (d, J=2.37 Hz, 1H), 9.24 (s, 1H).

Example 169N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)ureaExample 169A 1-[2-(dimethylamino)ethyl]-4-iodo-1H-indazol-3-amine

The desired product was prepared by substitutingN-(2-chloroethyl)-N,N-dimethylamine for 4-(2-chloroethyl)morpholine inExample 162A-C.

Example 169BN-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared as the bis(trifluoroacetate) salt bysubstituting Example 169A andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 152B (50 mg, 0.16 mmol) and Example 5A, respectively, inExample 152C. MS (ESI(+)) m/e 449 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ2.87 (s, 3H) 2.88 (s, 3H) 3.55 (q, J=5.65 Hz, 2H) 4.52 (t, J=6.27 Hz,2H) 6.87 (dd, J=6.95, 0.85 Hz, 1H) 7.01-7.05 (m, 1H) 7.30-7.32 (m, 2H)7.38-7.42 (m, 3H) 7.50 (d, J=8.48 Hz, 1H) 7.61 (d, J=8.48 Hz, 2H)7.73-7.75 (m, 1H) 9.01 (s, 1H) 9.04 (s, 1H).

Example 170N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamideExample 170A tert-butyl 2-(3-cyano-2-fluoro-4-iodophenoxy)ethylcarbamate

The desired product was prepared by substituting tert-butyl2-hydroxyethylcarbamate for 2-(4-morpholinyl)ethanol in Example 75A.R_(f)=0.8 (1:1 ethyl acetate/hexanes).

Example 170BN-[2-(3-cyano-2-fluoro-4-iodophenoxy)ethyl]methanesulfonamide

A mixture of Example 170A (317 mg, 0.78 mmol) in TFA (1 mL) and CH₂Cl₂(1 mL) was stirred at room temperature for 10 minutes and concentrated.The residue was partitioned between saturated NaHCO₃ anddichloromethane. The aqueous phase was extracted twice withdichloromethane and the combined organic extracts were dried (Na₂SO₄),filtered, and concentrated. The concentrate was dissolved in pyridine (5mL), treated with methanesulfonyl chloride (0.07 mL), stirred at roomtemperature for 6 hours, concentrated, and partitioned between ethylacetate and 1N HCl. The organic extract was dried (Na₂SO₄), filtered,and concentrated to provide the desired product. MS (ESI) m/e 383(M−H)⁻.

Example 170CN-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide

The desired product was prepared by substituting Example 170B for2-fluoro-6-iodobenzonitrile in Example 1A.

Example 170DN-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 170C for Example 152B in Example 152C. MS (APCI(+))m/e 513 (M+H)⁺; ¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H) 2.99 (s, 3H)3.43 (q, J=5.76 Hz, 2H) 4.22 (t, J=5.42 Hz, 2H) 4.35 (s, 2H) 6.70 (d,J=7.46 Hz, 1H) 6.80 (d, J=7.80 Hz, 1H) 6.80-6.83 (m, 1H) 7.08-7.19 (m,2H) 7.37 (d, J=8.81 Hz, 2H) 7.56 (d, J=8.81 Hz, 2H) 8.01 (dd, J=7.97,1.86 Hz, 1H) 8.52 (d, J=2.37 Hz, 1H) 9.17 (s, 1H) 11.77 (s, 1H).

Example 171 4-(1H-indol-5-yl)-1H-indazol-3-amine

The desired product was prepared by substituting 5-indolylboronic acidand Example 1A for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and Example 15F,respectively, in Example 15G. ¹H NMR (300 MHz, DMSO-d₆) δ 4.28 (s, 2H),6.50 (ddd, J=3.05, 2.03, 0.68 Hz, 1H), 6.80 (dd, J=6.27, 1.53 Hz, 1H),7.18 (dd, J=8.14, 1.70 Hz, 1H), 7.25 (m, 2H), 7.43 (m, 1H), 7.51 (d,J=8.14 Hz, 1H), 7.60 (m, 1H), 11.23 (s, 1H), 11.63 (s, 1H); MS (ESI(+))m/e 249 (M+H)⁺.

Example 172N-{4-[3-amino-1-(2-methoxyethyl)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)ureaExamples 172A and 172B2-[4-iodo-2-(2-methoxyethyl)-2H-indazol-3-yl]-1H-isoindole-1,3(2H)-dioneand2-[4-iodo-1-(2-methoxyethyl)-1H-indazol-3-yl]-1H-isoindole-1,3(2H)-dione

A mixture of Example 162A (1.2 g, 3.1 mmol), 1-bromo-2-methoxyethane(0.35 mL, 3.7 mmol) and K₂CO₃ (857 mg, 6.2 mmol) in DMF (15 mL) wasstirred overnight at rt, then concentrated to dryness. The residue waspartitioned between EtOAc and H₂O. The extract was dried (Na₂SO₄) andconcentrated, and the residue was purified by flash chromatography onsilica gel, eluting with 2% MeOH/CH₂Cl₂. The product was obtained as amixture of Examples 172A and 172B (˜3:1).

Example 172C and 172D 4-iodo-1-(2-methoxyethyl)-1H-indazol-3-amine and4-iodo-2-(2-methoxyethyl)-1H-indazol-3-amine

A mixture of the isomers 172A and 172B (970 mg, 2.2 mmol) was dissolvedin EtOH (10 mL) and the solution was chilled to 0° C. and treateddropwise with hydrazine monohydrate (0.58 mL), then stirred for 3 h atrt. The mixture was concentrated to dryness and the residue was purifiedby flash chromatography on silica gel, eluting with 0-4% MeOH/CH₂Cl₂. Amixture of isomers 172C and 172D was obtained. MS (ESI(+)) m/e 317.8(M+H)⁺.

Example 172E and 172F4-(4-aminophenyl)-1-(2-methoxyethyl)-1H-indazol-3-amine and4-(4-aminophenyl)-2-(2-methoxyethyl)-1H-indazol-3-amine

A mixture of Examples 172E and 172F was prepared by substituting amixture of Examples 172C and 172D for Example 15F in Example 15G. MS(ESI(+)) m/e 283.0 (M+H)⁺.

Example 172GN-{4-[3-amino-1-(2-methoxyethyl)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was obtained by substituting a mixture of Examples172E and 172F for Example 15G and 1-fluoro-2-isocyanato-4-methylbenzenefor 1-fluoro-3-isocyanatobenzene in Example 15H. Additionally, DMF wasused in place of CH₂Cl₂. The mixture was concentrated and the residuewas purified by preparative HPLC as in example 3 to provide the desiredproduct as the trifluoroacetate salt. ¹H NMR (300 MHz, DMSO-D₆) δ ppm2.28 (s, 3H) 3.21 (s, 3H) 3.69 (t, J=5.4 Hz, 2H) 4.32 (t, J=5.4 Hz, 2H)6.79-6.84 (m, 2H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.31 (dd, J=8.5, 6.8 Hz,1H) 7.38-7.43 (m, 3H) 7.59 (d, J=8.5 Hz, 2H) 8.01 (dd, J=7.8, 2.0 Hz,1H) 8.54 (d, J=2.4 Hz, 1H) 9.21 (s, 1H) MS (ESI(+)) m/e 434.0 (M+H)⁺.

Example 174N-(4-{3-amino-7-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 145A and1-isocyanato-3,5-dimethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. The productwas purified by preparative HPLC as in example 3. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 1.27 (s, 6H) 2.24 (s, 6H) 2.81 (s, 3H) 3.83 (t, J=6.4 Hz,2H) 4.35 (t, J=6.4 Hz, 2H) 6.62 (s, 1H) 6.68 (d, J=7.8 Hz, 1H) 6.83 (d,J=7.8 Hz, 1H) 7.09 (s, 2H) 7.34 (d, J=8.8 Hz, 2H) 7.55 (d, J=8.8 Hz, 2H)8.54 (s, 1H) 8.74 (s, 1H) 11.75-11.85 (br. s., 1H) MS (ESI(+)) m/e 556.3(M+H)⁺.

Example 175N-[4-(3-amino-1H-indazol-4-yl)-2,6-dimethylphenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting4-bromo-2,6-dimethylaniline for 4-bromo-2-ethylaniline in Examples149A-C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.25 (s, 3H) 2.30 (s, 6H)6.77-6.80 (m, 1H) 6.87 (dd, J=5.8, 2.4 Hz, 1H) 7.10 (dd, J=11.5, 8.5 Hz,1H) 7.20 (s, 2H) 7.33 (s, 1H) 7.35 (d. J=3.4 Hz, 1H) 7.98 (d, J=6.8 Hz,1H) 8.23 (s, 1H) 8.54-8.65 (br. s., 1H) 11.99-12.20 (br. s., 1H) MS(ESI(+)) m/e 404.2 (M+H)⁺.

Example 176N-[4-(3-amino-1H-indazol-4-yl)-2,6-dimethylphenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-(trifluoromethyl)benzene and 4-bromo-2,6-dimethylanilinefor 1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline,respectively, in Examples 149A-C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.30(s, 6H) 6.84 (dd, J=5.3, 2.5 Hz, 1H) 7.21 (s, 2H) 7.27-7.32 (m, 3H) 7.50(t, J=8.0 Hz, 1H) 7.62 (d, J=8.5 Hz, 1H) 7.96 (s, 1H) 8.03 (s, 1H) 9.17(s, 1H) 11.88-11.99 (m, 1H) MS (ESI(+)) m/e 440.2 (M+H)⁺.

Example 177N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-hydroxyphenyl)urea

The desired product was prepared by substituting4-iodo-1-isocyanatobenzene and 3-hydroxyaniline for1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline,respectively, in Examples 149A-C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.38(ddd, J=8.1, 2.3, 0.9 Hz, 1H) 6.82 (ddd, J=8.0, 2.0, 0.9 Hz, 1H) 6.86(dd, J=6.4, 1.7 Hz, 1H) 7.03-7.08 (m, 2H) 7.29-7.35 (m, 2H) 7.40 (d,J=8.5 Hz, 2H) 7.59 (d, J=8.8 Hz, 2H) 8.65 (s, 1H) 8.80 (s, 1H) 9.12-9.53(br. s., 1H) 11.80-12.39 (br. s., 1H) MS (ESI(+)) m/e 360.2 (M+H)⁺.

Example 178N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamideExample 178AN-(2-{[3-amino-4-(4-aminophenyl)-1H-indazol-7-yl]oxy}ethyl)methanesulfonamide

The desired product was prepared by substituting Example 170C and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1Aand 1B, respectively, in Example 1C.

Example 178BN-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide

The desired product was prepared by substituting Example 178A and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 2.99 (s, 3H) 3.44 (q, J=5.8 Hz, 2H)4.23 (t, J=5.4 Hz, 2H) 6.73 (d, J=7.8 Hz, 1H) 6.80 (d, J=7.8 Hz, 1H)6.84 (d, J=7.8 Hz, 1H) 7.12-7.19 (m, 2H) 7.25 (d, J=8.1 Hz, 1H) 7.31 (s,1H) 7.36 (d, J=8.5 Hz, 2H) 7.56 (d, J=8.5 Hz, 2H) 8.63 (s, 1H) 8.77 (s,1H), 11.91-12.07 (br. s., 1H) MS (ESI(+)) m/e 495.1 (M+H)⁺.

Example 179N-{2-[(3-amino-4-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide

The desired product was prepared by substituting Example 178A and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.99 (s, 3H) 3.44 (q, J=6.1 Hz, 2H) 4.22 (t, J=5.4Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 7.17 (t, J=6.1 Hz,1H) 7.38-7.42 (m, 3H) 7.48-7.54 (m, 1H) 7.58 (d, J=8.8 Hz, 2H) 8.65 (dd,J=7.5, 2.0 Hz, 1H) 8.94 (d, J=3.1 Hz, 1H) 9.29 (s, 1H) 11.87 (s, 1H) MS(ESI(+)) m/e 567.2 (M+H)⁺.

Example 180N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide

The desired product was prepared by substituting Example 178A and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.99 (s, 3H) 3.43 (q, J=5.8 Hz, 2H) 4.22 (t, J=5.4Hz, 2H) 6.71 (d, J=7.8 Hz, 1H) 6.81 (d, J=7.8 Hz, 1H) 7.03 (dt, J=6.7,2.3 Hz, 1H) 7.15-7.19 (m, 1H) 7.27-7.32 (m, 2H) 7.37 (d, J=8.5 Hz, 2H)7.57 (d, J=8.5 Hz, 2H) 7.73 (t, J=1.9 Hz, 1H) 8.86 (s, 1H) 8.93 (s, 1H)11.84 (s, 1H) MS (ESI(+))_(—)1515.1 (M+H)⁺.

Example 181N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide

The desired product was prepared by substituting Example 178A and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.99 (s, 3H) 3.43 (q, J=5.8 Hz, 2H) 4.22 (t, J=5.4Hz, 2H) 6.71 (d, J=7.5 Hz, 1H) 6.81 (d, J=7.8 Hz, 1H) 7.17 (t, J=5.8 Hz,1H) 7.30-7.34 (m, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.50-7.61 (m, 4H) 8.04 (t,J=2.2 Hz, 1H) 8.91 (s, 1H) 9.09 (s, 1H) 11.82 (s, 1H) MS (ESI(−)) m/e547.1 (M−H)⁻.

Example 182N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N′-(3-methylphenyl)urea Example182A 6-bromo-1H-indazol-3-amine

The desired product was prepared by substituting4-bromo-2-fluorobenzonitrile for 2-fluoro-6-iodobenzonitrile in Example1A. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.44 (s, 2H) 7.02 (dd, J=8.48, 1.70Hz, 1H) 7.41 (d, J=1.70 Hz, 1H) 7.63 (d, J=8.48 Hz, 1H) 11.49 (s, 1H).

Example 182CN-[4-(3-amino-1H-indazol-6-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 182A and 1B for1A and 5A respectively, in Example 5B. MS (ESI(+)Q1MS m/z 358 (M+H)⁺; ¹HNMR (500 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 5.34 (s, 2H) 6.79 (d, J=7.32Hz, 1H) 7.15-7.20 (m, 2H) 7.25 (d, J=8.24 Hz, 1H) 7.31 (s, 1H) 7.38 (s,1H) 7.55 (d, J=8.85 Hz, 2H) 7.62 (m, 2H) 7.72 (d, J=8.54 Hz, 1H) 8.75(s, 1H) 8.89 (s, 1H) 11.38 (s, 1H)

Example 1833-amino-N-(3-methylphenyl)-6-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazole-1-carboxamideExample 183A 6-(4-aminophenyl)-1H-indazol-3-amine

The desired product was prepared by substituting Example 182A forExample 1A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilinefor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.19 (s,2H) 5.27 (s, 2H) 6.64 (d, J=8.48 Hz, 2H) 7.10 (dd, J=8.48, 1.36 Hz, 1H)7.25 (s, 1H) 7.37 (d, J=8.48 Hz, 2H) 7.64 (d, J=8.48 Hz, 1H) 11.25 (s,1H).

Example 183B3-amino-N-(3-methylphenyl)-6-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazole-1-carboxamide

The desired product was prepared by substituting example 183A and1-isocyanato-3-methylbenzene for 15G and 1-fluoro-3-isocyanatobenzene,respectively in example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.29 (s,3H) 2.32 (s, 3H) 6.37 (s, 2H) 6.80 (d, J=7.1 Hz, 1H) 6.91 (d, J=7.5 Hz,1H) 7.17 (t, J=7.8 Hz, 1H) 7.22 (t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H)7.33 (s, 1H) 7.46-7.50 (m, 1H) 7.55-7.61 (m, 4H) 7.68 (d, J=8.8 Hz, 2H)7.95 (d, J=8.1 Hz, 1H) 8.39 (d, J=0.7 Hz, 1H) 8.62 (s, 1H) 8.83 (s, 1H)9.37 (s, 1H) MS (ESI(+)) m/e 490.0 (M+H)⁺.

Example 184N-[3-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea Example184AN-(3-methylphenyl)-N′-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

The desired product was prepared by substituting3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in Example 1B. MS(ESI(+)) m/e 352.9 (M+H)⁺.

Example 184BN-[3-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 184A forExample 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.27 (s, 3H)6.78-6.83 (m, 2H) 7.05-7.09 (m, 1H) 7.15 (t, J=7.8 Hz, 1H) 7.22 (d,J=8.1 Hz, 1H) 7.28-7.31 (m, 3H) 7.38-7.43 (m, 2H) 7.63 (s, 1H) 8.63 (s,1H) 8.81 (s, 1H) 11.74 (s, 1H) MS (ESI(+)) m/e 358.1 (M+H)⁺.

Example 185N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaExample 185A 4-iodo-7-methyl-1H-indazol-3-amine

The desired compound was prepared by substituting Example 15C for2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 273.8 (M+H)⁺.

Example 185B 4-(4-aminophenyl)-7-methyl-1H-indazol-3-amine

The desired product was prepared by substituting Example 185A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1Aand 1B, respectively, in Example 1C. MS (ESI(+)) m/e 239.0 (M+H)⁺.

Example 185CN-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 185B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.29 (s, 3H) 2.42 (s, 3H) 6.70 (d, J=7.1 Hz, 1H) 6.80 (d, J=7.5Hz, 1H) 7.05 (dd, J=7.1, 1.0 Hz, 1H) 7.16 (t, J=7.8 Hz, 1H) 7.25 (d,J=8.5 Hz, 1H) 7.32 (s, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H)8.63 (s, 1H) 8.77 (s, 1H) 11.75 (s, 1H) MS (ESI(+)) m/e 371.6 (M+H)⁺.

Example 186N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 185B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.45 (s, 3H) 6.80 (d, J=7.1 Hz, 1H) 7.00-7.06 (m, 1H) 7.15 (dd,J=7.1, 1.0 Hz, 1H) 7.28-7.32 (m, 2H) 7.39 (d, J=8.8 Hz, 2H) 7.60 (d,J=8.8 Hz, 2H) 7.73-7.75 (m, 1H) 8.98 (s, 1H) 9.01 (s, 1H) 12.01-12.46(br. s., 1H) MS (ESI(+)) m/e 382.0 (M+H)⁺.

Example 187N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 185B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.43 (s, 3H) 6.73 (d, J=7.1 Hz, 1H) 7.08 (d, J=7.1 Hz, 1H) 7.32(d, J=8.1 Hz, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.53 (t, J=7.8 Hz, 1H)7.58-7.61 (m, 3H) 8.04 (s, 1H) 8.94 (s, 1H) 9.11 (s, 1H) 11.87 (s, 1H)MS (ESI(+)) m/e 426.0 (M+H)⁺.

Example 188N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 185B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.43 (s, 3H) 6.71 (d, J=7.1 Hz, 1H) 7.06 (d, J=7.8 Hz, 1H)7.38-7.43 (m, 3H) 7.48-7.55 (m, 1H) 7.59 (d, J=8.5 Hz, 2H) 8.65 (dd,J=7.3, 2.2 Hz, 1H) 8.95 (d, J=2.7 Hz, 1H) 9.30 (s, 1H) 11.78 (s, 1H) MS(ESI(+)) m/e 444.1 (M+H)⁺.

Example 189N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 185B and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.44 (s, 3H) 6.76 (d, J=7.1 Hz, 1H) 7.11 (dd, J=7.3, 0.9 Hz, 1H)7.16 (ddd, J=7.8, 2.0, 1.0 Hz, 1H) 7.25 (t, J=8.0 Hz, 1H) 7.33 (ddd,J=8.1, 2.0, 1.0 Hz, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.59 (d, J=8.8 Hz, 2H)7.88 (t, J=1.9 Hz, 1H) 8.94 (s, 1H) 8.97 (s, 1H) 12.06 (s, 1H) MS(ESI(+)) m/e 463.0, 438.0 (M+H)⁺.

Example 190N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 185B forExample 15G in Example 15H. Additionally, DMF was used in place ofCH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 6.76-6.82 (m, 2H)7.13-7.17 (m, 2H) 7.32 (td, J=8.5, 6.8 Hz, 1H) 7.39 (d, J=8.8 Hz, 2H)7.52 (dt, J=12.1, 2.3 Hz, 1H) 7.60 (d, J=8.5 Hz, 2H) 8.96 (s, 1H) 9.03(s, 1H) 12.08-12.44 (br. s., 1H) MS (ESI(+)) m/e 376.1 (M+H)⁺.

Example 191N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 185B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.28 (s, 3H) 2.45 (s, 3H) 6.78 (d, J=6.8 Hz, 1H) 6.79-6.84 (m, 1H)7.08-7.15 (m, 2H) 7.39 (d, J=8.5 Hz, 2H) 7.59 (d, J=8.8 Hz, 2H) 8.01(dd, J=7.8, 1.7 Hz, 1H) 8.53 (d, J=2.4 Hz, 1H) 9.21 (s, 1H) 12.00-12.33(br. s., 1H) MS (ESI(+)) m/e 390.0 (M+H)⁺.

Example 192N-[4-(3-amino-7-methyl-1H-indazol-4-yl)phenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 185B and3-isocyanatobenzonitrile for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.44 (s, 3H) 6.77 (d, J=7.1 Hz, 1H) 7.12 (dd, J=7.1, 1.0 Hz, 1H)7.40 (d, J=8.5 Hz, 2H) 7.43 (dt, J=7.8, 1.4 Hz, 1H) 7.51 (t, J=8.0 Hz,1H) 7.60 (d, J=8.5 Hz, 2H) 7.70 (ddd, J=8.3, 2.2, 1.0 Hz, 1H) 8.01 (t,J=1.7 Hz, 1H) 9.05 (s, 1H) 9.14 (s, 1H) 11.98-12.22 (br. s., 1H) MSnm/>(ESI(+)) 383.1 (M+H)⁺.

Example 193N-[4-(3-amino-1H-indazol-4-yl)-2-(trifluoromethoxy)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting4-bromo-2-(trifluoromethoxy)aniline for 4-bromo-2-ethylaniline inExamples 149A-C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 6.82-6.91(m, 2H) 7.14 (dd, J=1.5, 8.1 Hz, 1H) 7.32 (d, J=1.0 Hz, 1H) 7.34 (s, 1H)7.47-7.52 (m, 2H) 8.03 (dd, J=8.0, 1.9 Hz, 1H) 8.42 (d, J=8.8 Hz, 1H)9.03 (s, 1H) 9.24 (d, J=2.4 Hz, 1H) 11.83-12.13 (br. s., 1H) MS (ESI(+))m/e 460.1 (M+H)⁺.

Example 194N-[5-(3-amino-1H-indazol-4-yl)pyridin-2-yl]-N′-(2-fluoro-5-methylphenyl)ureaExample 194A N-(5-bromopyridin-2-yl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting 2-amino-5-bromopyridineand 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI(+))m/e 324.0 (M+H)⁺.

Example 194BN-[5-(3-amino-1H-indazol-4-yl)pyridin-2-yl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 194A forExample 44A in Example 44B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.30 (s, 3H)6.83-6.92 (m, 2H) 7.15 (dd, J=11.2, 8.5 Hz, 1H) 7.34 (s, 1H) 7.35 (s,1H) 7.54 (d, J=8.5 Hz, 1H) 7.90 (dd, J=8.7, 2.5 Hz, 1H) 8.07 (dd, J=7.5,2.0 Hz, 1H) 8.38 (d, J=2.4 Hz, 1H) 9.95 (s, 1H) 10.88 (s, 1H) 12.02 (s,1H) MS (ESI(+)) me/377.1 (M+H)⁺.

Example 195N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaExample 195A 7-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting Example 26A for2-fluoro-6-iodobenzonitrile in Example 1A.

Example 195BN-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 195A forExample 1A andN-(2-fluoro-5-(trifluoromethyl)phenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.74 (dd,J=7.8, 4.1 Hz, 1H) 7.13 (dd, J=11.5, 7.8 Hz, 1H) 7.37-7.43 (m, 3H) 7.51(dd, J=10.9, 8.5 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H) 8.64 (dd, J=7.3, 2.2 Hz,1H) 8.96 (d, J=3.1 Hz, 1H) 9.32 (s, 1H) 12.25 (s, 1H) MS (ESI(+)) m/e448.0 (M+H)⁺.

Example 196N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(4-fluorophenyl)urea

The desired product was prepared by substituting Example 195A forExample 1A andN-(4-fluorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.74 (dd,J=7.8, 4.1 Hz, 1H) 7.11 (dd, J=7.8, 1.4 Hz, 1H) 7.15 (d, J=8.5 Hz, 2H)7.37 (d, J=8.5 Hz, 2H) 7.49 (dd, J=9.3, 4.9 Hz, 2H) 7.58 (d, J=8.5 Hz,2H) 8.77 (s, 1H) 8.83 (s, 1H) 12.29 (s, 1H) MS (ESI(+)) m/e 380.0(M+H)⁺.

Example 197N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(2-fluorophenyl)urea

The desired product was prepared by substituting Example 195A forExample 1A andN-(2-fluorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.98-7.06(m, 1H) 7.14 (dd, J=11.2, 7.8 Hz, 1H) 7.16 (dt, J=7.5, 1.4 Hz, 1H) 7.25(ddd, J=11.5, 8.1, 1.4 Hz, 1H) 7.33-7.38 (m, 1H) 7.39 (d, J=8.5 Hz, 2H)7.59 (d, J=8.5 Hz, 2H) 8.17 (td, J=8.3, 1.7 Hz, 1H) 8.61 (d, J=2.7 Hz,1H) 9.23 (s, 1H) 11.99-12.62 (br. s., 1H) MS (ESI(+)) m/e 380.0 (M+H)⁺.

Example 198N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea

The desired product was prepared by substituting Example 195A forExample 1A andN-(3-fluoro-4-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.17 (d,J=1.4 Hz, 3H) 6.73 (dd, J=7.8, 4.1 Hz, 1H) 7.05 (dd, J=8.3, 2.2 Hz, 1H)7.13 (dd, J=11.2, 7.8 Hz, 1H) 7.17 (t, J=8.7 Hz, 1H) 7.37 (d, J=8.5 Hz,2H) 7.45 (dd, J=12.5, 2.0 Hz, 1H) 7.58 (d, J=8.5 Hz, 2H) 8.84 (s, 1H)8.86 (s, 1H) 12.11-12.41 (br. s., 1H) MS (ESI(+)) m/e 394.1 (M+H)⁺.

Example 199 N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 195A forExample 1A andN-phenyl-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.74 (dd,J=7.8, 4.4 Hz, 1H) 6.98 (t, J=7.3 Hz, 1H) 7.13 (dd, J=11.2, 7.8 Hz, 1H)7.26-7.32 (m, 2H) 7.37 (d, J=8.5 Hz, 2H) 7.46-7.49 (m, 2H) 7.59 (d,J=8.5 Hz, 2H) 8.74 (s, 1H) 8.84 (s, 1H) 11.99-12.59 (br. s., 1H) MS(ESI(+)) m/e 362.0 (M+H)⁺.

Example 200N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamideExample 200AN-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}-1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substitutingtrifluoromethanesulfonic anhydride for methanesulfonyl chloride inExample 170B.

Example 200BN-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substituting Example 200A andExample 1B for Example 1A and Example 5A, respectively, in Example 5B.¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 3.65 (q, J=6.1 Hz, 2H) 4.24(t, J=5.3 Hz, 2H) 6.73 (d, J=7.8 Hz, 1H) 6.80 (d, J=6.8 Hz, 1H) 6.85 (d,J=7.8 Hz, 1H) 7.16 (t, J=7.6 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.31 (s, 1H)7.36 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.63 (s, 1H) 8.78 (s, 1H)9.52 (t, J=5.6 Hz, 1H) 11.83 (s, 1H) MS (ESI(+)) m/e 549.1 (M+H)⁺.

Example 201N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzenein Examples 44A-B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H)6.80-6.87 (m, 2H) 7.13 (dd, J=11.4, 8.3 Hz, 1H) 7.26-7.40 (m, 4H) 8.04(dd, J=8.1, 1.7 Hz, 1H) 8.32 (t, J=8.5 Hz, 1H) 9.04 (d, J=2.4 Hz, 1H)9.16 (d, J=2.7 Hz, 1H) 11.90 (s, 1H) MS (ESI(+)) m/e 394.2 (M+H)⁺.

Example 202N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substitutingN-(4-fluoro-3-trifluoromethylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.83 (dd,J=5.8, 2.3 Hz, 1H) 7.27-7.34 (m, 2H) 7.40-7.48 (m, 3H) 7.61 (d, J=8.8Hz, 2H) 7.63-7.69 (m, 1H) 8.03 (dd, J=6.4, 2.7 Hz, 1H) 8.99 (s, 1H) 9.13(s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e 430.0 (M+H)⁺.

Example 203N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substitutingN-(2-fluoro-3-trifluoromethylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.85 (dd,J=5.8, 2.0 Hz, 1H) 7.29-7.39 (m, 4H) 7.43 (d, J=8.5 Hz, 2H) 7.62 (d,J=8.5 Hz, 2H) 8.45-8.50 (m, 1H) 8.90 (d, J=2.7 Hz, 1H) 9.31 (s, 1H)12.01 (m, 1H) MS (ESI(+)) m/e 430.1 (M+H)⁺.

Example 204N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(4-bromo-2-fluorophenyl)urea

The desired product was prepared by substitutingN-(4-bromo-2-fluorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.83 (dd,J=5.8, 2.0 Hz, 1H) 7.30 (d, J=0.7 Hz, 1H) 7.31 (dd, J=13.2, 8.1 Hz, 1H)7.37 (ddd, J=8.8, 2.0, 1.4 Hz, 1H) 7.42 (d, J=8.8 Hz, 2H) 7.56-7.61 (m,3H) 8.16 (t, J=8.8 Hz, 1H) 8.71 (d, J=2.4 Hz, 1H) 9.25 (s, 1H) 11.97 (s,1H) MS (ESI(+)) m/e 440.0, 440.9 (M+H)⁺.

Example 205N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(5-fluoro-2-methylphenyl)urea

The desired product was prepared by substitutingN-(5-fluoro-2-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.24 (s,3H) 6.76 (td, J=8.5, 2.7 Hz, 1H) 6.87 (dd, J=6.1, 1.7 Hz, 1H) 7.16-7.24(m, 1H) 7.30-7.38 (m, 2H) 7.43 (d, J=8.5 Hz, 2H) 7.62 (d, J=8.5 Hz, 2H)7.87 (dd, J=12.2, 2.7 Hz, 1H) 8.12 (s, 1H) 9.34 (s, 1H) 11.94-12.25 (br.s., 1H) MS (ESI(+)) m/e 376.1 (M+H)⁺.

Example 206N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substitutingN-(4-fluoro-3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.22 (d,J=1.7 Hz, 3H) 6.84 (dd, J=6.1, 1.7 Hz, 1H) 7.06 (t, J=9.2 Hz, 1H)7.25-7.34 (m, 3H) 7.37-7.41 (m, 3H) 7.59 (d, J=8.5 Hz, 2H) 8.69 (s, 1H)8.84 (s, 1H) 11.86-12.20 (br. s., 1H) MS (ESI(+)) m/e 376.1 (M+H)⁺.

Example 207N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-phenylureaExample 207A 2-fluoro-6-iodo-3-(3-morpholin-4-ylpropoxy)benzonitrile

The desired product was prepared by substituting3-(4-morpholinyl)-propan-1-ol for 2-(4-morpholinyl)ethanol in Example75A. MS (ESI(+)) m/e 391 (M+H)⁺.

Example 207B4-(4-aminophenyl)-7-(3-morpholin-4-ylpropoxy)-1H-indazol-3-amine

The desired product was prepared by substituting Example 207A forExample 15E in Examples 15F-G.

Example 207CN-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-phenylurea

The desired product was prepared by substituting Example 207B andisocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D₆) δ ppm 2.18-2.23(m, 2H) 3.08-3.20 (m, 4H) 3.51-3.53 (m, 2H) 3.65-3.70 (m, 2H) 4.02-4.05(m, 2H) 4.24 (t, J=5.9 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz,1H) 6.98 (t, J=7.3 Hz, 1H) 7.27-7.31 (m, 2H) 7.35 (d, J=8.4 Hz, 2H) 7.48(d, J=7.8 Hz, 2H) 7.57 (d, J=8.4 Hz, 2H) 8.76 (s, 1H) 8.84 (s, 1H) 9.68(s, 1H) 11.86 (s, 1H) MS (ESI(+)) m/e 487.2 (M+H)⁺.

Example 208N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 207 for Example15G in Example 15H. ¹H NMR (500 MHz, DMSO-D₆) δ ppm 2.18-2.23 (m, 2H)3.08-3.18 (m, 4H) 3.51-3.53 (m, 2H) 3.65-3.70 (m, 2H) 4.02-4.05 (m, 2H)4.23 (t, J=5.8 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.78 (dt, J=8.1, 2.5 Hz,1H) 6.82 (d, J=7.8 Hz, 1H) 7.15 (dd, J=8.1, 1.3 Hz, 1H) 7.31 (dd,J=15.3, 8.4 Hz, 1H) 7.36 (d, J=8.7 Hz, 2H) 7.52 (dt, J=11.9, 2.2 Hz, 1H)7.57 (d, J=8.7 Hz, 2H) 8.96 (s, 1H) 9.06 (s, 1H) 9.71 (s, 1H) 11.86 (s,1H) MS (ESI(+)) m/e 505.1 (M+H)⁺.

Example 209N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 207B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.19-2.24 (m, 2H) 2.28 (s, 3H) 3.08-3.18 (m, 2H)3.42-3.45 (m, 2H) 3.50-3.55 (m, 2H) 3.68-3.72 (m, 2H) 4.03-4.08 (m, 2H)4.24 (t, J=5.8 Hz, 2H) 6.75 (d, J=7.8 Hz, 1H) 6.80-6.84 (m, 1H) 6.84 (d,J=7.8 Hz, 1H) 7.11 (dd, J=11.2, 8.4 Hz, 1H) 7.37 (d, J=8.4 Hz, 2H) 7.58(d, J=8.4 Hz, 2H) 7.99 (dd, J=7.8, 1.9 Hz, 1H) 8.56 (d, J=2.5 Hz, 1H)9.24 (s, 1H) 9.76-10.28 (br. s., 1H) MS (ESI(+)) m/e 519.2 (M+H)⁺.

Example 210N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 207B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.19-2.23 (m, 2H) 2.29 (s, 3H) 3.08-3.17 (m, 2H)3.43-3.51 (m, 4H) 3.66-3.70 (m, 2H) 4.02-4.05 (m, 2H) 4.24 (t, J=5.8 Hz,2H) 6.72 (d, J=7.8 Hz, 1H) 6.80 (d, J=8.1 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H)7.16 (t, J=7.6 Hz, 1H) 7.26 (d, J=8.1 Hz, 1H) 7.32 (s, 1H) 7.35 (d,J=8.4 Hz, 2H) 7.57 (d, J=8.4 Hz, 2H) 8.70 (s, 1H) 8.84 (s, 1H) 9.72 (s,1H) 11.88 (s, 1H) MS (ESI(+)) m/e 501.2 (M+H)⁺.

Example 211N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 207B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.18-2.24 (m, 2H) 3.08-3.18 (m, 2H) 3.42-3.45 (m,2H) 3.51-3.57 (m, 2H) 3.65-3.71 (m, 2H) 4.02-4.05 (m, 2H) 4.24 (t, J=5.8Hz, 2H) 6.73 (d, J=7.5 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H) 7.37-7.41 (m, 3H)7.49-7.53 (m, 1H) 7.59 (d, J=8.7 Hz, 2H) 8.64 (dd, J=7.3, 2.0 Hz, 1H)8.96 (d, J=2.8 Hz, 1H) 9.32 (s, 1H) 9.77 (s, 1H) 11.92 (s, 1H) MS(ESI(+)) m/e 573.1 (M+H)⁺.

Example 212N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 207B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.18-2.23 (m, 2H) 3.08-3.18 (m, 4H) 3.66-3.70 (m,4H) 4.02-4.05 (m, 2H) 4.24 (t, J=5.8 Hz, 2H) 6.73 (d, J=7.8 Hz, 1H) 6.82(d, J=7.8 Hz, 1H) 7.01-7.03 (m, 1H) 7.29-7.33 (m, 2H) 7.36 (d, J=8.4 Hz,2H) 7.58 (d, J=8.7 Hz, 2H) 7.74 (s, 1H) 9.00 (s, 1H) 9.07 (s, 1H) 9.74(s, 1H) 11.89 (s, 1H) MS (ESI(+)) m/e 521.1 (M+H)⁺.

Example 213N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 207B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.18-2.24 (m, 2H) 3.08-3.19 (m, 4H) 3.42-3.44 (m,2H) 3.66-3.70 (m, 2H) 4.02-4.04 (m, 2H) 4.24 (t, J=5.8 Hz, 2H) 6.74 (d,J=7.8 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H) 7.32 (d, J=7.8 Hz, 1H) 7.37 (d,J=8.4 Hz, 2H) 7.52 (t, J=8.0 Hz, 1H) 7.59-7.61 (m, 3H) 8.05 (s, 1H) 9.10(s, 1H) 9.28 (s, 1H) 9.78 (s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e 555.2(M+H)⁺.

Example 214N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substituting Example 200A forExample 1A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.28 (s, 3H)3.65 (q, J=4.9 Hz, 2H) 4.24 (t, J=5.3 Hz, 2H) 6.73 (d, J=7.8 Hz, 1H)6.78-6.82 (m, 1H) 6.84 (d, J=7.5 Hz, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H)7.37 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.01 (dd, J=8.0, 2.2 Hz,1H) 8.52 (d, J=2.7 Hz, 1H) 9.17 (s, 1H) 9.52 (t, J=5.8 Hz, 1H) 11.79 (s,1H) MS (ESI(+)) 567.0 m/e (M+H)⁺.

Example 215N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substituting Example 200A andN-(3-fluorophenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.65 (q, J=5.3 Hz, 2H) 4.23 (t, J=5.3 Hz, 2H) 6.71(d, J=7.8 Hz, 1H) 6.78 (td, J=8.5, 2.0 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H)7.13 (m, 1H) 7.30 (m, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.44-7.54 (m, 1H) 7.57(d, J=8.5 Hz, 2H) 8.86 (s, 1H) 8.95 (s, 1H) 9.52 (t, J=5.3 Hz, 1H) 11.72(s, 1H) MS (ESI(−)) m/e 550.9 (M−H)⁻.

Example 216N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamideExample 216AN-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide

The desired product was prepared by substituting phenylsulfonyl chloridefor methanesulfonyl chloride in Example 170B. MS (ESI(+)) m/e 459(M+H)⁺.

Example 216BN-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide

The desired product was prepared by substituting Example 216A andN-(2-fluoro-5-methylphenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.28 (s, 3H) 3.26 (q, J=5.6 Hz, 2H) 4.08 (t, J=5.6Hz, 2H) 6.67 (d, J=7.8 Hz, 1H) 6.70 (d, J=7.8 Hz, 1H) 6.79-6.82 (m, 1H)7.11 (dd, J=11.2, 8.4 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.55 (t, J=7.6 Hz,2H) 7.56 (d, J=8.5 Hz, 2H) 7.61 (t, J=7.2 Hz, 1H) 7.78 (t, J=6.1 Hz, 1H)7.84 (d, J=7.2 Hz, 2H) 8.00 (dd, J=8.0, 1.7 Hz, 1H) 8.50 (d, J=2.5 Hz,1H) 9.16 (s, 1H) 11.84 (s, 1H) MS (ESI(−)) m/e 573.2 (M−H)⁻.

Example 217N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide

The desired product was prepared by substituting Example 216A andN-(3-trifluoromethylphenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (500MHz, DMSO-D₆) δ ppm 3.26 (q, J=5.8 Hz, 2H) 4.10 (t, J=5.6 Hz, 2H) 6.70(d, J=7.8 Hz, 1H) 6.73 (d, J=7.8 Hz, 1H) 7.32 (d, J=7.5 Hz, 1H) 7.37 (d,J=8.4 Hz, 2H) 7.51-7.63 (m, 7H) 7.78 (t, J=6.1 Hz, 1H) 7.84 (d, J=8.7Hz, 2H) 8.04 (s, 1H) 8.93 (s, 1H) 9.11 (s, 1H) 12.01 (s, 1H) MS (ESI(+))m/e 611.1 (M+H)⁺.

Example 218N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide

The desired product was prepared by substituting Example 216A andN-(3-fluorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (500MHz, DMSO-D₆) δ ppm 3.26 (q, J=5.6 Hz, 2H) 4.09 (t, J=5.6 Hz, 2H) 6.70(d, J=7.8 Hz, 1H) 6.73 (d, J=7.8 Hz, 1H) 6.79 (td, J=8.4, 1.9 Hz, 1H)7.14 (dd, J=8.3, 1.1 Hz, 1H) 7.29-7.34 (m, 1H) 7.37 (d, J=8.7 Hz, 2H)7.49-7.58 (m, 5H) 7.61 (t, J=7.3 Hz, 1H) 7.78 (t, J=6.1 Hz, 1H)7.83-7.85 (m, J=8.4 Hz, 2H) 8.88 (s, 1H) 8.97 (s, 1H) 12.00 (s, 1H) MS(ESI(−)) m/e 559.0 (M−H)⁻.

Example 219N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide

The desired product was prepared by substituting Example 216A andN-(3-chlorophenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.26 (q, J=5.6 Hz, 2H) 4.10 (t, J=5.6 Hz, 2H)6.70-6.75 (m, 2H) 7.03 (td, J=4.3, 2.2 Hz, 1H) 7.27-7.32 (m, 2H) 7.37(d, J=8.5 Hz, 2H) 7.52-7.64 (m, 5H) 7.74-7.75 (m, 1H) 7.78-7.85 (m, 3H)8.92 (s, 1H) 8.98 (s, 1H) 12.09 (s, 1H) MS (ESI(+)) m/e 577.0 (M+H)⁺.

Example 220N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 220A 2-fluoro-3-formyl-6-iodobenzonitrile

LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a stirredsolution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol) in THF (200mL) at −78° C., and the mixture was stirred for 1 h. Methyl formate (5.0mL, 81.0 mmol) was added via syringe and the resulting mixture wasstirred at −78° C. for 30 min then at rt for 1 h. H₂O was added and themixture was extracted with EtOAc. The extracts were washed with brine,dried (MgSO₄) and concentrated. The residue was purified by flashchromatography on silica gel eluting with 20-25% EtOAc/hexanes to givethe desired product (8.01 g). MS (ESI(+)) m/e 274.9 (M+H)⁺.

Example 220B 2-fluoro-6-iodo-3-[(isopropylamino)methyl]benzonitrile

A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 mL) wastreated with isopropylamine (0.31 mL, 3.6 mmol) and sodiumcyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirredovernight at rt. HOAc (1 mL) was added and the reaction was stirred for5 h, then treated with 1N NaOH and extracted with EtOAc. The extractswere washed with brine, dried (MgSO₄) and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 8%MeOH/CH₂Cl₂ to give the desired product (372 mg). MS (ESI(+)) m/e 318.9(M+H)⁺.

Example 220C 4-iodo-7-[(isopropylamino)methyl]-1H-indazol-3-amine

The desired product was prepared by substituting Example 220B for2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 330.9 (M+H)⁺.

Example 220DN-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 220C andN-(2-fluoro-5-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.33 (d, J=6.4 Hz, 6H) 2.28 (s,3H) 3.39-3.51 (m, 1H) 4.39 (t, J=6.1 Hz, 2H) 6.79-6.84 (m, 1H) 6.90 (d,J=7.1 Hz, 1H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.39-7.45 (m, 3H) 7.61 (d,J=8.5 Hz, 2H) 7.99 (dd, J=7.8, 2.0 Hz, 1H) 8.55 (d, J=2.4 Hz, 1H)8.65-8.73 (m, 1H) 9.25 (s, 1H) 12.03 (s, 1H) MS (ESI(+)) m/e 447.1(M+H)⁺.

Example 221N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 220C andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.33 (d, J=6.8 Hz, 6H)3.37-3.49 (m, 1H) 4.38 (t, J=5.9 Hz, 2H) 6.90 (d, J=7.5 Hz, 1H) 7.03(dt, J=6.4, 2.4 Hz, 1H) 7.28-7.35 (m, 2H) 7.39-7.45 (m, 3H) 7.62 (d,J=8.5 Hz, 2H) 7.74-7.75 (m, 1H) 8.63-8.73 (m, 2H) 9.03 (s, 1H) 9.04 (s,1H) 12.03 (s, 1H) MS (ESI(+)) m/e 449.1 (M+H)⁺.

Example 222N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 220C andN-(3-trifluoromethylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.33 (d, J=6.4 Hz, 6H)3.39-3.51 (m, 1H) 4.39 (t, J=5.8 Hz, 2H) 6.91 (d, J=7.1 Hz, 1H) 7.32 (d,J=7.5 Hz, 1H) 7.39-7.45 (m, 3H) 7.53 (t, J=8.0 Hz, 1H) 7.59-7.66 (m, 3H)8.05 (s, 1H) 8.67-8.73 (m, 2H) 9.14 (s, 1H) 9.28 (s, 1H) 12.05 (s, 1H)MS (ESI(−)) m/e 481.0 (M−H)⁻.

Example 223N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 220C andN-(3-methylphenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.33 (d, J=6.4 Hz, 6H) 2.29 (s,3H) 3.39-3.51 (m, 1H) 4.36-4.40 (m, 2H) 6.80 (d, J=7.8 Hz, 1H) 6.90 (d,J=7.1 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 7.26 (d, J=8.5 Hz, 1H) 7.32 (s, 1H)7.39 (d, J=8.8 Hz, 2H) 7.44 (d, J=7.5 Hz, 1H) 7.62 (d, J=8.8 Hz, 2H)8.69 (m, 2H) 8.75 (s, 1H) 8.94 (s, 1H) 12.03 (s, 1H) MS (ESI(+)) m/e429.1 (M+H)⁺.

Example 224N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 220C andN-(4-fluoro-3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.33 (d, J=6.4 Hz, 6H) 2.22 (d,J=1.7 Hz, 3H) 3.39-3.51 (m, 1H) 4.36-4.40 (m, 2H) 6.90 (d, J=7.1 Hz, 1H)7.06 (t, J=9.2 Hz, 1H) 7.28 (ddd, J=8.4, 4.8, 3.1 Hz, 1H) 7.37-7.45 (m,4H) 7.61 (d, J=8.5 Hz, 2H) 8.64-8.74 (m, 2H) 8.79 (s, 1H) 8.95 (s, 1H)12.04 (s, 1H) MS (ESI(+)) m/e 447.1 (M+H)⁺.

Example 225N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 225A 2-fluoro-3-(hydroxymethyl)-6-iodobenzonitrile

A solution of Example 220A (5.0 g, 18 mmol) in MeOH (100 mL) at 0° C.was treated with NaBH₄ (822 mg, 22 mmol) and the mixture was stirred for1 h at 0° C. Acetone was added and the mixture was stirred for 5 min,then concentrated to dryness. The residue was partitioned between H₂Oand EtOAc. The extracts were washed with brine, dried (MgSO₄) andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 3:2 hexanes/EtOAc to give the desired product (3.14g). R_(f)=0.38 (3:2 hexane:EtOAc).

Example 225B 3-[(4-chlorophenoxy)methyl]-2-fluoro-6-iodobenzonitrile

The desired product was prepared by substituting Example 225A and4-chlorophenol for Example 68A and 2-(4-morpholinyl)ethanol,respectively, in Example 75A. Additionally, diisopropyl azodicarboxylatewas substituted for DEAD. MS (ESI(−)) m/e 385.8 (M−H)⁻.

Example 225C 7-[(4-chlorophenoxy)methyl]-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting Example 225B for2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 399.9 (M+H)⁺.

Example 225DN-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 225C forExample 1A and in Example 5B. Additionally, toluene/EtOH/H₂O (2:1:1) wassubstituted for DME/water as solvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm2.28 (s, 3H) 5.33 (s, 2H) 6.79-6.83 (m, 2H) 7.09 (d, J=9.2 Hz, 2H)7.06-7.15 (m, 1H) 7.33-7.38 (m, 3H) 7.41 (d, J=8.5 Hz, 2H) 7.60 (d,J=8.5 Hz, 2H) 8.01 (dd, J=7.8, 2.0 Hz, 1H) 8.54 (d, J=2.7 Hz, 1H) 9.22(s, 1H) 12.00 (s, 1H) MS (ESI(+)) m/e 516.1 (M+H)⁺.

Example 226N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 226C andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.33 (s, 2H) 6.82 (d, J=7.5 Hz,1H) 7.01-7.05 (m, 1H) 7.08 (d, J=8.8 Hz, 2H) 7.28-7.32 (m, 2H) 7.33-7.38(m, 3H) 7.41 (d, J=8.8 Hz, 2H) 7.60 (d, J=8.8 Hz, 2H) 7.73-7.74 (m, 1H)8.93 (s, 1H) 8.96 (s, 1H) 12.01 (s, 1H) MS (ESI(+)) m/e 518.5 (M+H)⁺.

Example 227N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 225C andN-(3-trifluoromethylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.32 (s, 2H) 6.82 (d, J=7.1 Hz,1H) 7.08 (d, J=8.8 Hz, 2H) 7.31-7.37 (m, 4H) 7.41 (d, J=8.5 Hz, 2H) 7.53(t, J=8.0 Hz, 1H) 7.59-7.63 (m, 3H) 8.04 (s, 1H) 8.96 (s, 1H) 9.11 (s,1H) 11.96 (s, 1H) MS (ESI(+)) m/e 522.0 (M+H)⁺.

Example 228N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 225C andN-(3-methylphenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 5.33 (s, 2H) 6.80(d, J=7.5 Hz, 1H) 6.83 (d, J=7.1 Hz, 1H) 7.08 (d, J=8.8 Hz, 2H) 7.17 (t,J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.32 (s, 1H) 7.33-7.41 (m, 5H) 7.60(d, J=8.8 Hz, 2H) 8.65 (s, 1H) 8.82 (s, 1H) 12.08 (s, 1H) MS (ESI(+))m/e 498.1 (M+H)⁺.

Example 229N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 225C andN-(4-fluoro-3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B.Additionally, toluene/EtOH/H₂O (2:1:1) was substituted for DME/water assolvent. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.22 (d, J=1.7 Hz, 3H) 5.33 (s,2H) 6.83 (d, J=7.1 Hz, 1H) 7.01-7.11 (m, 3H) 7.25-7.31 (m, 1H) 7.33-7.41(m, 6H) 7.59 (d, J=8.8 Hz, 2H) 8.68 (s, 1H) 8.82 (s, 1H) 12.05 (s, 1H)MS (ESI(+)) m/e 516.1 (M+H)⁺.

Example 230N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 230A 2-fluoro-6-iodo-3-[3-(1H-pyrrol-1-yl)propoxy]benzonitrile

The desired product was prepared by substituting3-pyrrol-1-yl-propan-1-ol for 2-(4-morpholinyl)ethanol in Example 75A.

Example 230B 4-iodo-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-3-amine

The desired product was prepared by substituting Example 230A for2-fluoro-6-iodobenzonitrile in Example 1A. MS (ESI(+)) m/e 383 (M+H)⁺.

Example 230CN-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 230B forExample 1A in Example 5B. ¹H NMR (500 MHz, DMSO-D₆) δ ppm 2.14-2.23 (m,2H) 2.27 (s, 3H) 4.01 (t, J=6.1 Hz, 2H) 4.19 (t, J=6.9 Hz, 2H) 4.31 (s,2H) 5.97 (t, J=2.2 Hz, 2H) 6.66 (d, J=7.5 Hz, 1H) 6.71 (d, J=7.8 Hz, 1H)6.76 (t, J=2.2 Hz, 2H) 6.78-6.81 (m, 1H) 7.10 (dd, J=11.2, 8.4 Hz, 1H)7.35 (d, J=8.4 Hz, 2H) 7.55 (d, J=8.4 Hz, 2H) 7.99 (dd, J=8.0, 2.0 Hz,1H) 8.49 (d, J=2.2 Hz, 1H) 9.14 (s, 1H) 11.90 (s, 1H) MS (ESI(+)) m/e499.1 (M+H)⁺.

Example 2314-(1H-indol-5-yl)-7-[3-(1H-pyrrol-1-yl)propoxyl]-1H-indazol-3-amine

The desired product was prepared by substituting Example 230B andindole-5-boronic acid for Example 1A and Example 5A, respectively, inExample 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.16-2.24 (m, 2H) 4.02 (t,J=6.1 Hz, 2H) 4.21 (t, J=6.6 Hz, 2H) 4.29 (s, 2H) 5.98 (t, J=2.0 Hz, 2H)6.47-6.49 (m, 1H) 6.67 (d, J=7.5 Hz, 1H) 6.72 (d, J=7.8 Hz, 1H) 6.78 (t,J=2.0 Hz, 2H) 7.14 (dd, J=8.3, 1.5 Hz, 1H) 7.41 (t, J=2.7 Hz, 1H) 7.49(d, J=8.1 Hz, 1H) 7.56 (s, 1H) 11.19 (s, 1H) 11.86 (s, 1H) MS (ESI(+))m/e 372.1 (M+H)⁺.

Example 232N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 230B andN-(3-methylphenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.16-2.24 (m, 2H) 2.29 (s, 3H) 4.02 (t, J=5.9 Hz,2H) 4.20 (t, J=6.8 Hz, 2H) 5.98 (t, J=2.2 Hz, 2H) 6.68 (d, J=7.8 Hz, 1H)6.74 (d, J=7.8 Hz, 1H) 6.77 (t, J=2.0 Hz, 2H) 6.80 (d, J=7.1 Hz, 1H)7.16 (t, J=7.6 Hz, 1H) 7.25 (d, J=8.1 Hz, 1H) 7.32 (s, 1H) 7.35 (d,J=8.8 Hz, 2H) 7.56 (d, J=8.8 Hz, 2H) 8.63 (s, 1H) 8.76 (s, 1H) 12.05 (s,1H) MS (ESI(+)) m/e 481.1 (M+H)⁺.

Example 233N-(4-{3-amino-7-[3-(1H-pyrrol-1-yl)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 230B andN-(3-chlorophenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.15-2.23 (m, 2H) 4.01 (t, J=5.9 Hz, 2H) 4.20 (t,J=6.8 Hz, 2H) 4.33 (s, 2H) 5.98 (t, J=2.2 Hz, 2H) 6.66 (d, J=7.5 Hz, 1H)6.72 (d, J=7.8 Hz, 1H) 6.77 (t, J=2.2 Hz, 2H) 7.02 (dt, J=6.4, 2.2 Hz,1H) 7.28 (m, 2H) 7.36 (d, J=8.5 Hz, 2H) 7.56 (d, J=8.5 Hz, 2H) 7.72-7.74(m, 1H) 8.85 (s, 1H) 8.92 (s, 1H) 11.93 (s, 1H) MS (ESI(−)) m/e 499.3(M−H)⁻.

Example 234N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamideExample 234AN-{2-[(3-amino-4-iodo-1H-indazol-7-yl)oxy]-ethyl}thiophene-2-sulfonamide

The desired product was prepared by substituting 2-thiophenesulfonylchloride for methanesulfonyl chloride in Example 170B. MS (ESI(+)) m/e465 (M+H)⁺.

Example 234BN-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide

The desired product was prepared by substituting Example 234A forExample 1A in Example 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.28 (s, 3H)3.30-3.34 (m, 2H) 4.14 (t, J=5.9 Hz, 2H) 6.68 (d, J=7.5 Hz, 1H) 6.74 (m,J=7.5 Hz, 1H) 6.79-6.83 (m, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.17 (dd,J=5.1, 3.7 Hz, 1H) 7.36 (d, J=8.8 Hz, 2H) 7.56 (d, J=8.8 Hz, 2H) 7.65(dd, J=3.7, 1.4 Hz, 1H) 7.92-8.02 (m, 3H) 7.98 (d, J=6.4 Hz, 1H) 8.01(dd, J=7.8, 2.0 Hz, 1H) 8.51 (d, J=2.4 Hz, 1H) 9.17 (s, 1H) 11.84 (s,1H) MS (ESI(+)) m/e 580.6 (M+H)⁺.

Example 235N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide

The desired product was prepared by substituting Example 234A andN-(3-methylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 3.33 (q, J=5.8 Hz, 2H) 4.14 (t, J=5.8Hz, 2H) 6.66-6.84 (m, 3H) 7.16 (t, J=7.8 Hz, 1H) 7.17 (dd, J=5.1, 3.7Hz, 1H) 7.25 (d, J=8.8 Hz, 1H) 7.31 (s, 1H) 7.35 (d, J=8.5 Hz, 2H) 7.56(d, J=8.5 Hz, 2H) 7.65 (dd, J=3.7, 1.4 Hz, 1H) 7.93 (dd, J=5.1, 1.4 Hz,1H) 7.97 (t, J=5.9 Hz, 1H) 8.63 (s, 1H) 8.77 (s, 1H) 11.91 (s, 1H) MS(ESI(+)) m/e 563.0 (M+H)⁺.

Example 236N-(2-{[3-amino-4-(1H-indol-5-yl)-1H-indazol-7-yl]oxy}ethyl)thiophene-2-sulfonamide

The desired product was prepared by substituting Example 234A andindole-5-boronic acid for Example 1A and Example 5A, respectively, inExample 5B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 3.33 (q, J=5.4 Hz, 2H) 4.16(t, J=5.6 Hz, 2H) 6.49-6.49 (m, 1H) 6.74 (d, J=7.8 Hz, 1H) 6.78 (d,J=7.8 Hz, 1H) 7.15 (dd, J=8.5, 1.7 Hz, 1H) 7.18 (dd, J=4.8, 3.7 Hz, 1H)7.41 (t, J=2.7 Hz, 1H) 7.49 (d, J=8.1 Hz, 1H) 7.57 (d, J=1.4 Hz, 1H)7.65 (dd, J=3.7, 1.4 Hz, 1H) 7.94 (dd, J=5.1, 1.4 Hz, 1H) 7.98 (t, J=5.9Hz, 1H) 11.20 (s, 1H) 11.98 (s, 1H) MS (ESI(+)) m/e 454.0 (M+H)⁺.

Example 237N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 237A 3-[3-(diethylamino)propoxy]-2-fluoro-6-iodobenzonitrile

The desired product was prepared by substituting3-(diethylamino)-propan-1-ol for 2-(4-morpholinyl)ethanol in Example75A.

Example 237B4-(4-aminophenyl)-7-[3-(diethylamino)propoxy]-1H-indazol-3-amine

The desired product was prepared by substituting Example 237A forExample 15E in Examples 15F-G. MS (ESI(+)) m/e 354 (M+H)⁺.

Example 237CN-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 237B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 1.25 (t, J=7.3 Hz, 6H) 2.11-2.20 (m, 2H) 2.28 (s,3H) 3.16-2.35 (m, 4H) 3.31-3.41 (m, 2H) 4.24 (t, J=5.8 Hz, 2H) 6.71 (d,J=7.5 Hz, 1H) 6.79-6.84 (m, 2H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.36 (d,J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.00 (dd, J=7.8, 2.0 Hz, 1H) 8.52(d, J=2.4 Hz, 1H) 9.07 (s, 1H) 9.18 (s, 1H) 11.93 (s, 1H) MS (APCI(+))m/e 505.4 (M+H)⁺.

Example 238N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 237B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 1.25 (t, J=7.29 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.25(m, 4H) 3.34-3.14 (m, 2H) 4.24 (t, J=5.8 Hz, 2H) 6.71 (d, J=7.8 Hz, 1H)6.81 (d, J=7.8 Hz, 1H) 7.03 (dt, J=6.4, 2.4 Hz, 1H) 7.26-7.32 (m, 2H)7.36 (d, J=8.8 Hz, 2H) 7.57 (d, J=8.8 Hz, 2H) 7.73-7.74 (m, 1H) 8.92 (s,1H) 8.98 (s, 1H) 9.05 (s, 1H) 11.92 (s, 1H) MS (ESI(+)) m/e 506.9(M+H)⁺.

Example 239N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 237B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 1.24 (t, J=7.3 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.25(m, 4H) 3.31-3.37 (m, 2H) 4.24 (t, J=5.6 Hz, 2H) 6.71 (d, J=7.8 Hz, 1H)6.81 (m, J=7.8 Hz, 1H) 7.32 (d, J=7.1 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H)7.50-7.61 (m, 4H) 8.04 (s, 1H) 8.95 (s, 1H) 9.04 (s, 1H) 9.13 (s, 1H)11.92 (s, 1H) MS (ESI(+)) m/e 541.2 (M+H)⁺.

Example 240N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 237B forExample 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.25 (t,J=7.3 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.24 (m, 4H) 3.34-3.43 (m, 2H) 4.24(t, J=5.6 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.76-6.82 (m, 1H) 6.81 (d,J=7.8 Hz, 1H) 7.14 (ddd, J=8.1, 2.0, 0.7 Hz, 1H) 7.28-7.35 (m, 1H) 7.36(d, J=8.8 Hz, 2H) 7.52 (dt, J=12.0, 2.3 Hz, 1H) 7.57 (d, J=8.8 Hz, 2H)8.92 (s, 1H) 9.01 (s, 1H) 9.06 (s, 1H) 11.94 (s, 1H) MS (APCI(−)) m/e489.3 (M−H)⁻.

Example 241N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-(trifluoromethyl)benzene for 1-isocyanato-3-methylbenzenein Examples 44A-B. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 4.37 (s, 2H)6.80-6.86 (m, 1H) 7.26-7.35 (m, 4H) 7.39 (dd, J=12.2, 1.7 Hz, 1H)7.54-7.56 (m, 2H) 8.06 (s, 1H) 8.26 (t, J=8.5 Hz, 1H) 8.76 (d, J=2.4 Hz,1H) 9.47 (s, 1H) 11.77 (s, 1H) MS (ESI(+)) m/e 430.0 (M+H)⁺.

Example 242N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for1-isocyanato-3-methylbenzene in Examples 44A-B. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 4.37 (s, 2H) 6.83 (dd, J=4.4, 3.7 Hz, 1H) 7.25-7.29 (m,3H) 7.38 (dd, J=12.0, 1.9 Hz, 1H) 7.46 (t, J=9.8 Hz, 1H) 7.61-7.66 (m,1H) 8.05 (dd, J=6.4, 2.7 Hz, 1H) 8.23 (t, J=8.5 Hz, 1H) 8.75 (d, J=1.7Hz, 1H) 9.45 (s, 1H) 11.77 (s, 1H) MS (ESI(+)) m/e 448.0 (M+H)⁺.

Example 243N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)ureaExample 243A 3-fluoro-1,1′-biphenyl-2-carbonitrile

The desired product was prepared by substituting2-fluoro-6-iodobenzonitrile for Example 1A and phenylboronic acid forExample 1B in Example 1C. Additionally, toluene/EtOH/H₂O (3:2:1) wassubstituted for DME/H₂O as the solvent.

Example 243B 3-fluoro-4-iodo-1,1′-biphenyl-2-carbonitrile

A solution of Example 243A (6.8 g, 34.5 mmol) in THF (110 mL) at −78° C.under nitrogen atmosphere was treated dropwise with LDA (2.0 M solutionin THF) and stirred for 1 h, then a solution of iodine in THF (30 mL)was added via cannula over about 10 min. The thick mixture was allowedto warm to rt and stirred for 1 h, then treated with saturated aqueousNa2SO3 solution (10 mL). The mixture was concentrated to remove the THF,then H2O was added and the mixture was extracted with EtOAc. Theextracts were washed with brine, dried (MgSO4) and concentrated. Theresidue was purified by flash chromatography on silica gel, eluting withEtOAc/hexanes (1:7), and the resulting solid was triturated with hexanesand EtOAc to give the desired product (6.8 g). R_(f)=0.44 (7:1hexane:EtOAc)

Example 243C 3-fluoro-4-iodo-4′-nitro-1,1′-biphenyl-2-carbonitrile

A solution of Example 243B (2.77 g, 8.6 mmol) in 1,2-dichloroethane (50mL) under nitrogen atmosphere was treated with nitroniumtetrafluoroborate (85% technical grade, 2.0 g, 12.9 mmol) and themixture was stirred for 3.5 h, at which time an additional portion ofnitronium tetrafluoroborate (700 mg, 5.3 mmol) was added. The reactionwas stirred for another 2 h, then poured over ice, and once melted themixture was neutralized with sat. NaHCO3 solution. The mixture wasextracted with EtOAc, and the extracts were washed with brine, dried(MgSO4) and concentrated. The residue was purified by flashchromatography on silica gel, eluting with hexanes/EtOAc (4:1) to givethe desired product (1.84 g). MS (ESI(−)) m/e 367.9 (M−H)⁻.

Example 243D3-fluoro-4′-nitro-4-pyridin-3-yl-1,1′-biphenyl-2-carbonitrile

The desired product was prepared by substituting Example 243C andpyridine-3-boronic acid for Examples 1A and 1B, respectively, in Example1C. Additionally, PdCl2(dppf) was used in place of Pd(PPh3)4. MS(ESI(+)) m/e 320.0 (M+H)⁺.

Example 243E 4-(4-aminophenyl)-7-pyridin-3-yl-1H-indazol-3-amine

The desired product was prepared by substituting Example 243D for2-fluoro-6-iodobenzonitrile in Example 1A. In addition to pyrazolecyclization, nitro reduction was also accomplished in this reaction. MS(ESI(+)) m/e 302.0 (M+H)⁺.

Example 243FN-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 243E and1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.23 (d, J=1.7 Hz, 3H) 6.97 (d, J=7.5 Hz, 1H) 7.06 (t, J=9.2 Hz,1H) 7.29 (ddd, J=8.7, 4.5, 3.1 Hz, 1H) 7.39 (dd, J=6.8, 2.8 Hz, 1H)7.43-7.47 (m, 3H) 7.62 (d, J=8.5 Hz, 2H) 7.69-7.80 (m, 1H) 8.32 (d,J=7.8 Hz, 1H) 8.67-8.80 (m, 1H) 8.71 (s, 1H) 8.87 (s, 1H) 8.90-9.15 (m,1H) 11.81-12.42 (br. s., 1H) MS (ESI(+)) m/e 453.1 (M+H)⁺.

Example 244N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 243E and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 6.96 (d, J=7.5 Hz, 1H) 7.02-7.05 (m, 1H) 7.28-7.35 (m, 2H)7.44-7.47 (m, 3H) 7.63 (d, J=8.8 Hz, 2H) 7.66-7.72 (m, 1H) 7.74-7.75 (m,1H) 8.27 (d, J=7.5 Hz, 1H) 8.61-8.85 (m, 1H) 8.93-9.04 (m, 3H)11.73-12.36 (br. s., 1H) MS (ESI(+)) m/e 455.1 (M+H)⁺.

Example 245N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 243E and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 6.97 (d, J=7.1 Hz, 1H) 7.33 (d, J=7.5 Hz, 1H) 7.44-7.47 (m, 3H)7.53 (t, J=7.8 Hz, 1H) 7.60-7.70 (m, 4H) 8.05 (s, 1H) 8.26 (d, J=8.1 Hz,1H) 8.61-8.81 (m, 1H) 8.89-9.08 (m, 2H) 9.15 (s, 1H) 11.79-12.29 (br.s., 1H) MS (ESI(+)) e 489.1 (M+H)⁺.

Example 246N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 243E and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.29 (s, 3H) 6.79-6.84 (m, 1H) 6.96 (d, J=7.5 Hz, 1H) 7.12 (dd,J=11.4, 8.3 Hz, 1H) 7.44-7.47 (m, 3H) 7.63 (d, J=8.8 Hz, 2H) 7.65-7.73(m, 1H) 8.01 (dd, J=8.0, 1.9 Hz, 1H) 8.26 (d, J=7.8 Hz, 1H) 8.55 (d,J=2.4 Hz, 1H) 8.63-8.82 (m, 1H) 8.88-9.11 (m, 1H) 9.24 (s, 1H)11.79-12.33 (br. s., 1H) MS (ESI(+)) m/e 453.1 (M+H)⁺.

Example 247N-[4-(3-amino-7-pyridin-3-yl-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 243E and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 6.95 (d, J=7.5 Hz, 1H) 7.40-7.49 (m, 4H) 7.61-7.70 (m, 4H) 8.04(dd, J=6.4, 2.7 Hz, 1H) 8.19-8.23 (m, 1H) 8.67 (dd, J=4.8, 1.4 Hz, 1H)8.94-8.97 (m, 1H) 9.00 (s, 1H) 9.12 (s, 1H) 12.02 (s, 1H) MS (ESI(+))m/e 507.1 (M+H)⁺.

Example 248N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)ureaExample 248A 3-[3-(dimethylamino)propoxy]-2-fluoro-6-iodobenzonitrile

The desired product was prepared by substituting3-(dimethylamino)-propan-1-ol for 2-(4-morpholinyl)ethanol in Example75A. MS (ESI(+)) m/e 349 (M+H)⁺.

Example 248B4-(4-aminophenyl)-7-[3-(dimethylamino)propoxy]-1H-indazol-3-amine

The desired product was prepared by substituting Example 248A forExample 15E in Examples 15F-G. MS (ESI(+)) m/e 326 (M+H)⁺.

Example 248CN-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 248B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H) 2.28 (s, 3H) 2.86 (d, J=5.1 Hz,6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.8 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.80(d, J=7.1 Hz, 1H) 6.82 (d, J=7.8 Hz, 1H) 7.16 (t, J=7.8 Hz, 1H) 7.25 (d,J=8.5 Hz, 1H) 7.32 (s, 1H) 7.34 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H)8.68 (s, 1H) 8.83 (s, 1H) 9.40 (s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e459.2 (M+H)⁺.

Example 249N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 248B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H) 2.28 (s, 3H) 2.86 (d, J=4.8 Hz,6H) 3.34-3.42 (m, 2H) 4.22 (t, J=5.9 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H)6.79-6.83 (m, 2H) 7.12 (dd, J=11.2, 8.5 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H)7.57 (d, J=8.5 Hz, 2H) 8.00 (dd, J=8.0, 1.9 Hz, 1H) 8.53 (d, J=2.4 Hz,1H) 9.19 (s, 1H) 9.41 (s, 1H) 11.94 (s, 1H) MS (ESI(+)) m/e 477.1(M+H)⁺.

Example 250N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 248B forExample 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.13-2.22(m, 2H) 2.86 (d, J=4.8 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.9 Hz, 2H)6.73 (d, J=7.5 Hz, 1H) 6.79 (td, J=8.6, 2.5 Hz, 1H) 6.83 (d, J=7.8 Hz,1H) 7.14 (ddd, J=8.1, 2.0, 1.0 Hz, 1H) 7.26-7.37 (m, 1H) 7.36 (d, J=8.5Hz, 2H) 7.52 (dt, J=12.0, 2.3 Hz, 1H) 7.58 (d, J=8.5 Hz, 2H) 8.98 (s,1H) 9.07 (s, 1H) 9.44 (s, 1H) 11.99 (s, 1H) MS (ESI(+)) m/e 463.2(M+H)⁺.

Example 251N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 248 and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H) 2.86 (d, J=4.8 Hz, 6H) 3.34-3.41(m, 2H) 4.22 (t, J=5.8 Hz, 2H) 6.73 (d, J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz,1H) 7.03 (ddd, J=6.1, 3.1, 2.4 Hz, 1H) 7.27-7.32 (m, 2H) 7.36 (d, J=8.5Hz, 2H) 7.58 (d, J=8.5 Hz, 2H) 7.73-7.75 (m, 1H) 8.98 (s, 1H) 9.04 (s,1H) 9.41 (s, 1H) 11.96 (s, 1H) MS (ESI(+)) m/e 479.1 (M+H)⁺.

Example 252N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 248B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H) 2.86 (d, J=4.8 Hz, 6H) 3.34-3.41(m, 2H) 4.22 (t, J=5.9 Hz, 2H) 6.72 (d, J=7.8 Hz, 1H) 6.82 (d, J=7.8 Hz,1H) 7.32 (d, J=7.5 Hz, 1H) 7.36 (d, J=8.8 Hz, 2H) 7.50-7.61 (m, 4H) 8.05(s, 1H) 8.98 (s, 1H) 9.16 (s, 1H) 9.38 (s, 1H) 11.92 (s, 1H) MS (ESI(+))m/e 513.1 (M+H)⁺.

Example 253N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 248B and1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.13-2.19 (m, 2H) 2.22 (d, J=1.7 Hz, 3H) 2.86 (d,J=5.1 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.9 Hz, 2H) 6.72 (d, J=7.8Hz, 1H) 6.81 (d, J=7.8 Hz, 1H) 7.05 (t, J=9.2 Hz, 1H) 7.28 (ddd, J=8.8,4.1, 2.7 Hz, 1H) 7.33-7.39 (m, 3H) 7.56 (d, J=8.5 Hz, 2H) 8.72 (s, 1H)8.83 (s, 1H) 9.41 (s, 1H) 11.95 (s, 1H) MS (ESI(+)) m/e 477.2 (M+H)⁺.

Example 254N-{4-[3-amino-7-(3-morpholin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 207B and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.18-2.23 (m, 2H) 3.06-3.19 (m, 4H) 3.42-3.46 (m,2H) 3.65-3.70 (m, 2H) 4.00-4.07 (m, 2H) 4.24 (t, J=5.8 Hz, 2H) 6.73 (d,J=7.8 Hz, 1H) 6.83 (d, J=7.8 Hz, 1H) 7.16 (ddd, J=8.1, 1.9, 0.9 Hz, 1H)7.25 (t, J=8.1 Hz, 1H) 7.32-7.38 (m, 3H) 7.58 (d, J=8.7 Hz, 2H) 7.88 (t,J=1.9 Hz, 1H) 8.99 (s, 1H) 9.04 (s, 1H) 9.73 (s, 1H) 11.91 (s, 1H) MS(ESI(+)) m/e 565.1, 567.1 (M+H)⁺.

Example 255N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(3-methylphenyl)ureaExample 255A3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine

The desired product was prepared by substituting4-bromo-3-fluoro-phenylamine for Example 149A in Example 149B. Themixture was heated at 85° C. overnight and the desired product waspurified by flash chromatography using 30% ethyl acetate in hexanes. MS(ESI(+) m/e 238 (M+H)⁺.

Example 255BN-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 255A and1-isocyanato-3-methylbenzene for 4-bromo-2-ethylaniline and1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A. MS(ESI(+) m/e 371 (M+H)⁺.

Example 255CN-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 255B forExample 1B in Example 1C. ¹H NMR (400 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H),6.81-6.85 (m, 2H), 7.18 (t, J=7.83 Hz, 1H), 7.25 (d, J=1.84 Hz, 1H),7.27 (d, J=1.84 Hz, 1H), 7.30-7.34 (m, 4H), 7.64 (dd, J=12.73, 1.99 Hz,1H), 8.74 (s, 1H), 9.04 (s, 1H); MS (ESI(+) m/e 376 (M+H)⁺.

Example 256N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 255A for4-bromo-2-ethylaniline in Example 149A and then substituting the productfor Example 1B in Example 1C. ¹H NMR (400 MHz, DMSO-D₆) δ ppm 2.49 (s,3H), 7.02-7.05 (m, 1H), 7.08 (t, J=3.84 Hz, 1H), 7.32 (dd, J=11.20, 8.44Hz, 1H), 7.43-7.45 (m, 1H), 7.52-7.57 (m, 3H), 7.85 (dd, J=12.43, 1.69Hz, 1H), 8.17 (d, J=7.98 Hz, 1H), 8.80 (d, J=2.15 Hz, 1H), 9.61 (s, 1H);MS (ESI(+) m/e 394 (M+H)⁺.

Example 257N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 255A and1-chloro-3-isocyanatobenzene for 4-bromo-2-ethylaniline and1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A andthen substituting the product for Example 1B in Example 1C. ¹H NMR (400MHz, DMSO-D₆) δ ppm 6.81 (dd, J=4.91, 2.46 Hz, 1H), 7.03-7.06 (m, 1H),7.27-7.35 (m, 6H), 7.62 (dd, J=12.43, 1.99 Hz, 1H), 7.72 (t, J=1.99 Hz,1H), 9.02 (s, 1H), 9.12 (s, 1H); MS (ESI(+) m/e 396 (M+H)⁺.

Example 258N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 255A and1-fluoro-4-isocyanato-2-methylbenzene for 4-bromo-2-ethylaniline and1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A andthen substituting the product for Example 1B in Example 1C. ¹H NMR (400MHz, DMSO-D₆) δ ppm 2.22 (s, 3H), 6.87 (t, J=3.84 Hz, 1H), 7.06 (t,J=9.05 Hz, 1H), 7.27-7.38 (m, 6H), 7.63 (dd, J=12.58, 1.53 Hz, 1H), 8.79(s, 1H), 9.07 (s, 1H); MS (ESI(+) m/e 394 (M+H)⁺.

Example 259N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 255A and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene,respectively, in Example 149A and then substituting the product forExample 1B in Example 1C. ¹H NMR (400 MHz, DMSO-D₆) δ ppm 6.89 (t,J=3.84 Hz, 1H), 7.28 (dd, J=8.44, 1.99 Hz, 1H), 7.34-7.38 (m, 3H),7.42-7.45 (m, 1H), 7.50-7.54 (m, 1H), 7.66 (dd, J=12.43, 1.99 Hz, 1H),8.61 (dd, J=7.21, 1.99 Hz, 1H), 9.03 (d, J=2.15 Hz, 1H), 9.54 (s, 1H);MS (ESI(+) m/e 448 (M+H)⁺.

Example 260N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 255A and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene,respectively, in Example 149A and then substituting the product forExample 1B in Example 1C. ¹H NMR (400 MHz, DMSO-D₆) δ ppm 6.84 (t,J=3.99 Hz, 1H), 7.29-7.36 (m, 4H), 7.46 (t, J=9.82 Hz, 1H), 7.62 (dd,J=12.73, 1.69 Hz, 1H), 7.68 (m, 1H), 8.02 (dd, J=6.60, 2.92 Hz, 1H),9.21 (s, 2H); MS (ESI(+) m/e 448 (M+H)⁺.

Example 261N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)ureaExample 261A 4-(4-aminophenyl)-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 95A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1Aand 1B, respectively, in Example 1C. MS (ESI(+)) m/e 226 (M+H)⁺.

Example 261BN-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 261A and1-isocyanato-3,5-dimethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.24 (s, 6H) 5.22 (s, 2H) 6.63 (s, 1H) 7.10 (s, 2H)7.14 (d, J=6.8 Hz, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.48 (d, J=8.1 Hz, 1H)7.56-7.64 (m, 3H) 8.57 (s, 1H) 8.83 (s, 1H) MS (ESI(+)) m/e 373.1(M+H)⁺.

Example 262 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 261A andisocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.22 (s,2H) 6.99 (t, J=7.5 Hz, 1H) 7.14 (d, J=7.1 Hz, 1H) 7.30 (t, J=8.0 Hz, 2H)7.44 (d, J=8.5 Hz, 2H) 7.46-7.50 (m, 3H) 7.58 (dd, J=8.3, 7.3 Hz, 1H)7.63 (d, J=8.5 Hz, 2H) 8.74 (s, 1H) 8.87 (s, 1H) MS (ESI(+)) m/e 345.0(M+H)⁺.

Example 263N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 261A and1-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.25 (s, 3H) 5.22 (s, 2H) 7.10 (d, J=8.5 Hz, 2H)7.13 (d, J=6.8 Hz, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.43 (d, J=8.5 Hz, 2H)7.48 (d, J=8.1 Hz, 1H) 7.55-7.63 (m, 3H) 8.62 (s, 1H) 8.83 (s, 1H) MS(ESI(+)) m/e 359.0 (M+H)⁺.

Example 264N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-cyanophenyl)urea

The desired product was prepared by substituting Example 261A and3-isocyanatobenzonitrile for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.14 (dd, J=7.1, 0.7 Hz, 1H) 7.42-7.50(m, 4H) 7.51 (t, J=8.0 Hz, 1H) 7.59 (dd, J=8.5, 7.5 Hz, 1H) 7.64 (d,J=8.5 Hz, 2H) 7.71 (ddd, J=8.2, 2.1, 1.2 Hz, 1H) 8.00 (t, J=1.9 Hz, 1H)9.05 (s, 1H) 9.09 (s, 1H) MS (ESI(+)) m/e 370.0 (M+H)⁺.

Example 265 5N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 261A and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.14 (d, J=7.1 Hz, 1H) 7.45 (d, J=8.5Hz, 2H) 7.45 (t, J=9.7 Hz, 1H) 7.49 (dd, J=8.1, 0.7 Hz, 1H) 7.59 (dd,J=8.5, 7.5 Hz, 1H) 7.62-7.70 (m, 3H) 8.03 (dd, J=6.4, 2.7 Hz, 1H) 9.01(s, 1H) 9.11 (s, 1H) MS (ESI(+)) m/e 431.0 (M+H)⁺.

Example 266N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 261A and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.13-7.18 (m, 2H) 7.26 (t, J=8.0 Hz,1H) 7.34 (ddd, J=8.1, 2.0, 1.4 Hz, 1H) 7.44 (d, J=8.5 Hz, 2H) 7.49 (dd,J=8.5, 0.9 Hz, 1H) 7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H)7.88 (t, J=1.9 Hz, 1H) 8.95 (s, 1H) 8.96 (s, 1H) MS (ESI(+)) m/e 422.9,424.8 (M+H)⁺.

Example 267N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 261A and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.75 (s, 2H) 7.03 (dt, J=6.4, 2.7 Hz, 1H) 7.14 (dd,J=7.1, 0.7 Hz, 1H) 7.28-7.35 (m, 2H) 7.44 (d, J=8.5 Hz, 2H) 7.48 (d,J=8.1 Hz, 1H) 7.59 (dd, J=8.1, 7.5 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 7.73(t, J=2.0 Hz, 1H) 8.96 (app. s., 2H) MS (ESI(+)) m/e 379.0 (M+H)⁺.

Example 268N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 261A and3-ethyl-1-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 1.19 (t, J=7.5 Hz, 3H) 2.59 (q, J=7.5 Hz, 2H) 5.22(s, 2H) 6.84 (d, J=7.5 Hz, 1H) 7.14 (d, J=7.1 Hz, 1H) 7.19 (t, J=7.6 Hz,1H) 7.27 (d, J=7.8 Hz, 1H) 7.34 (s, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.48 (d,J=8.1 Hz, 1H) 7.56-7.64 (m, 3H) 8.67 (s, 1H) 8.84 (s, 1H) MS (ESI(+))m/e 373.0 (M+H)⁺.

Example 269N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 261A and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.15 (d, J=7.1 Hz, 1H) 7.44-7.50 (m,3H) 7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.63-7.71 (m, 6H) 9.02 (s, 1H) 9.18 (s,1H) MS (ESI(+)) m/e 413.0 (M+H)⁺.

Example 270N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea

The desired product was prepared by substituting Example 261A and1-fluoro-5-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.17 (d, J=1.4 Hz, 3H) 5.22 (s, 2H) 7.05 (dd, J=8.3,2.2 Hz, 1H) 7.12-7.21 (m, 2H) 7.42-7.50 (m, 4H) 7.56-7.64 (m, 3H) 8.84(s, 1H) 8.90 (s, 1H) MS (ESI(+)) m/e 377.1 (M+H)⁺.

Example 271N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 261A forExample 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.22 (s, 2H)6.77-6.83 (m, 1H) 7.13-7.18 (m, 2H) 7.32 (td, J=8.1, 7.1 Hz, 1H) 7.44(d, J=8.8 Hz, 2H) 7.48 (dd, J=8.5, 1.0 Hz, 1H) 7.52 (dt, J=11.9, 2.4 Hz,1H) 7.59 (dd, J=8.1, 7.5 Hz, 1H) 7.63 (d, J=8.8 Hz, 2H) 8.94 (s, 1H)8.98 (s, 1H) MS (ESI(+)) m/e 363.0 (M+H)⁺.

Example 272 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3,5-difluorophenyl)urea

The desired product was prepared by substituting Example 261A and1,3-difluoro-5-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.21 (s, 2H) 6.81 (tt, J=9.4, 2.3 Hz, 1H) 7.14 (dd,J=7.1, 0.7 Hz, 1H) 7.22 (dd, J=10.0, 2.3 Hz, 2H) 7.45 (d, J=8.5 Hz, 2H)7.49 (dd, J=8.5, 0.7 Hz, 1H) 7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.63 (d, J=8.5Hz, 2H) 9.05 (s, 1H) 9.16 (s, 1H) MS (ESI(+)) m/e 381.0 (M+H)⁺.

Example 273N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methoxyphenyl)urea

The desired product was prepared by substituting Example 261A and3-isocyanato-1-methoxybenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.74 (s, 3H) 5.22 (s, 2H) 6.57 (dd, J=8.0, 2.2 Hz,1H) 6.96 (dd, J=8.1, 1.4 Hz, 1H) 7.14 (d, J=6.8 Hz, 1H) 7.19 (t, J=8.1Hz, 1H) 7.21 (t, J=2.2 Hz, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.48 (d, J=7.8 Hz,1H) 7.58 (dd, J=8.1, 7.1 Hz, 1H) 7.62 (d, J=8.5 Hz, 2H) 8.75 (s, 1H)8.86 (s, 1H) MS (ESI(+)) m/e 375.1 (M+H)⁺.

Example 274N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(4-methoxyphenyl)urea

The desired product was prepared by substituting Example 261A and4-isocyanato-1-methoxybenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.72 (s, 3H) 5.22 (s, 2H) 6.88 (d, J=8.8 Hz, 2H)7.13 (dd, J=7.1, 0.7 Hz, 1H) 7.38 (d, J=8.8 Hz, 2H) 7.42 (d, J=8.5 Hz,2H) 7.48 (dd, J=8.5, 0.7 Hz, 1H) 7.58 (dd, J=8.5, 7.5 Hz, 1H) 7.62 (d,J=8.5 Hz, 2H) 8.54 (s, 1H) 8.79 (s, 1H) MS (ESI(+)) m/e 375.1 (M+H)⁺.

Example 275 N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]urea

A solution of Example 261A (45 mg, 0.2 mmol) and sodium isocyanate (26mg, 0.4 mmol) in HOAc (0.5 mL) and H₂O (0.5 mL) was stirred overnight atrt, then diluted with water. The precipitated solid was collected byfiltration and recrystallized from THF/hexanes to give an offwhite solid(35 mg, 65%). ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.20 (s, 2H) 5.92 (s, 2H)7.11 (dd, J=7.3, 0.9 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.46 (dd, J=8.5, 1.0Hz, 1H) 7.57 (d, J=8.5 Hz, 2H) 7.57 (dd, J=8.1, 7.1 Hz, 1H) 8.72 (s, 1H)MS (ESI(+)) m/e 269.0 (M+H)⁺.

Example 276N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-nitrophenyl)urea

The desired product was prepared by substituting Example 261A and1-nitro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.21 (s, 2H) 7.15 (d, J=6.8 Hz, 1H) 7.45-7.50 (m,3H) 7.57-7.62 (m, 2H) 7.66 (d, J=8.5 Hz, 2H) 7.75 (dd, J=7.8, 1.7 Hz,1H) 7.84 (dd, J=8.1, 2.4 Hz, 1H) 8.59 (t, J=2.2 Hz, 1H) 9.09 (s, 1H)9.34 (s, 1H) MS (ESI(+)) m/e 390.0 (M+H)⁺.

Example 277N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(4-fluorophenyl)urea

The desired product was prepared by substituting Example 261A and1-fluoro-4-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.21 (s, 2H) 7.11-7.17 (m, 3H) 7.40-7.51 (m, 5H)7.58 (dd, J=8.1, 7.1 Hz, 1H) 7.63 (d, J=8.8 Hz, 2H) 8.80 (s, 1H) 8.90(s, 1H) MS (ESI(+)) m/e 363.0 (M+H)⁺.

Example 278N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(2-fluorophenyl)urea

The desired product was prepared by substituting Example 261A and1-fluoro-2-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 6.99-7.06 (m, 1H) 7.13-7.19 (m, 2H)7.25 (ddd, J=11.7, 8.1, 1.5 Hz, 1H) 7.45 (d, J=8.8 Hz, 2H) 7.49 (dd,J=8.5, 1.0 Hz, 1H) 7.59 (dd, J=8.5, 7.5 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H)8.17 (td, J=8.3, 1.7 Hz, 1H) 8.62 (d, J=2.4 Hz, 1H) 9.27 (s, 1H) MS(ESI(+)) m/e 363.0 (M+H)⁺.

Example 279N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chloro-4-fluorophenyl)urea

The desired product was prepared by substituting Example 261A and1-chloro-2-fluoro-5-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.14 (dd, J=7.3, 0.9 Hz, 1H) 7.34 (m,2H) 7.44 (d, J=8.5 Hz, 2H) 7.48 (dd, J=8.3, 0.9 Hz, 1H) 7.58 (dd, J=8.5,7.1 Hz, 1H) 7.63 (d, J=8.5 Hz, 2H) 7.81-7.84 (m, 1H) 8.95 (s, 1H) 8.97(s, 1H) MS (ESI(+)) m/e 397.0 (M+H)⁺.

Example 280N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chloro-4-methoxyphenyl)urea

The desired product was prepared by substituting Example 261A and1-chloro-5-isocyanato-2-methoxybenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.82 (s, 3H) 5.22 (s, 2H) 7.10 (d, J=9.2 Hz, 1H)7.14 (dd, J=7.1, 1.0 Hz, 1H) 7.29 (dd, J=9.2, 2.5 Hz, 1H) 7.43 (d, J=8.5Hz, 2H) 7.48 (dd, J=8.3, 1.0 Hz, 1H) 7.58 (dd, J=8.1, 7.1 Hz, 1H) 7.62(d, J=8.5 Hz, 2H) 7.68 (d, J=2.5 Hz, 1H) 8.71 (s, 1H) 8.87 (s, 1H) MS(ESI(+)) m/e 409.0 (M+H)⁺.

Example 281N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-(dimethylamino)phenyl]urea

The desired product was prepared by substituting Example 261A and4-dimethylamino-1-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.84 (s, 6H) 5.21 (s, 2H) 6.71 (d, J=9.2 Hz, 2H)7.13 (dd, J=7.1, 1.0 Hz, 1H) 7.28 (d, J=9.2 Hz, 2H) 7.41 (d, J=8.5 Hz,2H) 7.47 (dd, J=8.5, 1.0 Hz, 1H) 7.58 (dd, J=8.5, 7.1 Hz, 1H) 7.61 (d,J=8.5 Hz, 2H) 8.36 (s, 1H) 8.73 (s, 1H) MS (ESI(+)) m/e 388.1 (M+H)⁺.

Example 282N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-1,3-benzodioxol-5-ylurea

The desired product was prepared by substituting Example 261A and5-isocyanato-benzo[1,3]dioxole for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.21 (s, 2H) 5.98 (s, 2H) 6.78 (dd, J=8.5, 2.0 Hz,1H) 6.84 (d, J=8.5 Hz, 1H) 7.13 (dd, J=7.1, 1.0 Hz, 1H) 7.22 (d, J=2.0Hz, 1H) 7.42 (d, J=8.5 Hz, 2H) 7.48 (dd, J=8.1, 1.0 Hz, 1H) 7.58 (dd,J=8.1, 7.5 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H) 8.62 (s, 1H) 8.80 (s, 1H) MS(ESI(+)) m/e 389.0 (M+H)⁺.

Example 283N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting Example 261A and4-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.14 (dd, J=7.1, 1.0 Hz, 1H) 7.30 (d,J=8.8 Hz, 2H) 7.44 (d, J=8.5 Hz, 2H) 7.48 (dd, J=8.5, 0.7 Hz, 1H) 7.59(dd, J=8.3, 7.3 Hz, 1H) 7.59 (d, J=8.8 Hz, 2H) 7.63 (d, J=8.5 Hz, 2H)8.93 (s, 1H) 8.96 (s, 1H) MS (ESI(−)) m/e 426.9 (M−H)⁻.

Example 284N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting Example 261A and2-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.23 (s, 2H) 7.11 (td, J=7.6, 2.0 Hz, 1H) 7.15 (d,J=7.1 Hz, 1H) 7.36 (td, J=8.1, 1.4 Hz, 1H) 7.39 (ddd, J=6.6, 3.1, 1.5Hz, 1H) 7.44-7.50 (m, 3H) 7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.65 (d, J=8.5Hz, 2H) 8.28 (dd, J=8.3, 1.5 Hz, 1H) 8.55 (s, 1H) 9.48 (s, 1H) MS(ESI(+)) m/e 429.0 (M+H)⁺.

Example 285N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 261A and1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.22 (s, 2H) 7.15 (dd, J=7.1, 1.0 Hz, 1H) 7.45-7.51(m, 3H) 7.59 (dd, J=8.5, 7.1 Hz, 1H) 7.65-7.69 (m, 3H) 8.16 (s, 2H) 9.20(s, 1H) 9.47 (s, 1H) MS (ESI(+)) m/e 481.0 (M+H)⁺.

Example 286N-[4-(3-amino-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chloro-4-methylphenyl)urea

The desired product was prepared by substituting Example 261A and1-chloro-5-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.27 (s, 3H) 5.22 (s, 2H) 7.14 (dd, J=7.1, 1.0 Hz,1H) 7.21 (dd, J=8.5, 2.0 Hz, 1H) 7.26 (d, J=8.5 Hz, 1H) 7.44 (d, J=8.8Hz, 2H) 7.48 (dd, J=8.5, 0.7 Hz, 1H) 7.58 (dd, J=8.5, 7.5 Hz, 1H) 7.63(d, J=8.8 Hz, 2H) 7.71 (d, J=2.0 Hz, 1H) 8.84 (s, 1H) 8.91 (s, 1H) MS(ESI(+)) m/e 393.1 (M+H)⁺.

Example 287N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 100C and1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.97 (s, 3H) 5.21 (s, 2H) 7.06 (d, J=8.1 Hz, 1H)7.17 (d, J=8.1 Hz, 1H) 7.41 (d, J=8.5 Hz, 2H) 7.63 (d, J=8.5 Hz, 2H)7.66 (s, 1H) 8.16 (s, 2H) 9.16 (s, 1H) 9.45 (s, 1H) MS (ESI(+)) m/e511.0 (M+H)⁺.

Example 288N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting Example 100C and4-isocyanato-1-(trifluoromethoxy)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 7.04 (d, J=8.1 Hz, 1H)7.16 (d, J=8.1 Hz, 1H) 7.30 (d, J=8.8 Hz, 2H) 7.39 (d, J=8.5 Hz, 2H)7.58 (d, J=8.8 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H) 8.89 (s, 1H) 8.94 (s, 1H)MS (ESI(+)) m/e 459.0 (M+H)⁺.

Example 289N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 100C forExample 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 3.96 (s, 3H)5.21 (s, 2H) 6.80 (td, J=8.5, 2.4 Hz, 1H) 7.05 (d, J=7.8 Hz, 1H)7.12-7.18 (m, 2H) 7.28-7.36 (m, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.51 (dt,J=11.9, 2.2 Hz, 1H) 7.60 (d, J=8.5 Hz, 2H) 8.91 (s, 1H) 8.96 (s, 1H) MS(ESI(+)) m/e 393.0 (M+H)⁺.

Example 290N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methoxyphenyl)urea

The desired product was prepared by substituting Example 100C and3-isocyanato-1-methoxybenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.74 (s, 3H) 3.96 (s, 3H) 5.21 (s, 2H) 6.57 (dd,J=8.3, 2.5 Hz, 1H) 6.95 (dd, J=7.8, 1.5 Hz, 1H) 7.04 (d, J=7.8 Hz, 1H)7.15-7.22 (m, 3H) 7.38 (d, J=8.5 Hz, 2H) 7.59 (d, J=8.5 Hz, 2H) 8.73 (s,1H) 8.82 (s, 1H) MS (ESI(+)) m/e 405.0 (M+H)⁺.

Example 291N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3,5-difluorophenyl)urea

The desired product was prepared by substituting Example 100C and1,3-difluoro-5-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 6.80 (tt, J=9.3, 2.4 Hz,1H) 7.05 (d, J=8.1 Hz, 1H) 7.17 (d, J=8.1 Hz, 1H) 7.19-7.26 (m, 2H) 7.40(d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H) 9.01 (s, 1H) 9.14 (s, 1H) MS(ESI(+)) m/e 411.1 (M+H)⁺.

Example 292N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 100C and1-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.25 (s, 3H) 3.96 (s, 3H) 5.20 (s, 2H) 7.04 (d,J=8.1 Hz, 1H) 7.09 (d, J=8.1 Hz, 2H) 7.16 (d, J=8.1 Hz, 1H) 7.35 (d,J=8.1 Hz, 2H) 7.37 (d, J=8.5 Hz, 2H) 7.58 (d, J=8.5 Hz, 2H) 8.60 (s, 1H)8.78 (s, 1H) MS (ESI(+)) m/e 389.1 (M+H)⁺.

Example 293N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 100C and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 7.05 (d, J=7.8 Hz, 1H)7.14-7.18 (m, 2H) 7.25 (t, J=8.0 Hz, 1H) 7.33 (ddd, J=8.0, 2.0, 1.2 Hz,1H) 7.39 (d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H)8.91 (s, 1H) 8.92 (s, 1H) MS (ESI(+)) m/e 451.0, 453.0 (M+H)⁺.

Example 294N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 100C and1-isocyanato-3,5-dimethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.24 (s, 6H) 3.96 (s, 3H) 5.20 (s, 2H) 6.63 (s, 1H)7.04 (d, J=8.1 Hz, 1H) 7.09 (s, 2H) 7.16 (d, J=8.1 Hz, 1H) 7.37 (d,J=8.5 Hz, 2H) 7.59 (d, J=8.5 Hz, 2H) 8.55 (s, 1H) 8.79 (s, 1H) MS(ESI(+)) m/e 403.1 (M+H)⁺.

Example 295N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-(dimethylamino)phenyl]urea

The desired product was prepared by substituting Example 100C and4-dimethylamino-1-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.84 (s, 6H) 3.96 (s, 3H) 5.20 (s, 2H) 6.71 (d,J=9.2 Hz, 2H) 7.03 (d, J=8.1 Hz, 1H) 7.16 (d, J=8.1 Hz, 1H) 7.28 (d,J=9.2 Hz, 2H) 7.35 (d, J=8.5 Hz, 2H) 7.57 (d, J=8.5 Hz, 2H) 8.35 (s, 1H)8.68 (s, 1H) MS (ESI(+)) m/e 418.1 (M+H)⁺.

Example 296N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-1,3-benzodioxol-5-ylurea

The desired product was prepared by substituting Example 100C and5-isocyanato-benzo[1,3]dioxole for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 5.97 (s, 2H) 6.78 (dd,J=8.5, 2.0 Hz, 1H) 6.84 (d, J=8.5 Hz, 1H) 7.04 (d, J=8.1 Hz, 1H) 7.16(d, J=8.1 Hz, 1H) 7.22 (d, J=2.0 Hz, 1H) 7.37 (d, J=8.5 Hz, 2H) 7.57 (d,J=8.5 Hz, 2H) 8.60 (s, 1H) 8.76 (s, 1H) MS (ESI(+)) m/e 419.1 (M+H)⁺.

Example 297N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methylphenyl)ureaExample 297A 4-iodo-7-methyl-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 15C for2-bromo-6-fluorobenzonitrile in Example 95A. MS (ESI(+)) m/e 274.8(M+H)⁺.

Example 297B 4-(4-aminophenyl)-7-methyl-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 297A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1Aand 1B, respectively, in Example 1C. MS (ESI(+)) m/e 240.0 (M+H)⁺.

Example 297CN-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 297B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 2.45 (s, 3H) 5.20 (s, 2H) 6.80 (d,J=7.5 Hz, 1H) 7.03 (d, J=7.1 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 7.25 (d,J=8.5 Hz, 1H) 7.31 (s, 1H) 7.38 (dd, J=7.5, 1.0 Hz, 1H) 7.40 (d, J=8.5Hz, 2H) 7.61 (d, J=8.5 Hz, 2H) 8.64 (s, 1H) 8.83 (s, 1H) MS (ESI(+)) m/e373.1 (M+H)⁺.

Example 298N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 297B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.02-7.05 (m, 2H)7.27-7.32 (m, 2H) 7.37-7.44 (m, 3H) 7.62 (d, J=8.8 Hz, 2H) 7.73-7.74 (m,1H) 8.94 (s, 1H) 8.95 (s, 1H) MS (ESI(+)) m/e 393.0 (M+H)⁺.

Example 299N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 297B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.28 (s, 3H) 2.45 (s, 3H) 5.20 (s, 2H) 6.79-6.84 (m,1H) 7.04 (d, J=7.1 Hz, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.37-7.43 (m,3H) 7.61 (d, J=8.5 Hz, 2H) 8.00 (dd, J=7.6, 1.9 Hz, 1H) 8.54 (d, J=2.4Hz, 1H) 9.24 (s, 1H) MS (ESI(+)) m/e 391.1 (M+H)⁺.

Example 300N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 297B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.46 (s, 3H) 5.20 (s, 2H) 7.05 (d, J=7.5 Hz, 1H)7.38-7.45 (m, 4H) 7.48-7.55 (m, 1H) 7.63 (d, J=8.5 Hz, 2H) 8.64 (dd,J=7.3, 2.2 Hz, 1H) 8.97 (s, 1H) 9.37 (s, 1H) MS (ESI(+)) m/e 445.0(M+H)⁺.

Example 301N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 297B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J=7.1 Hz, 1H)7.32 (d, J=7.8 Hz, 1H) 7.38 (dd, J=7.3, 0.9 Hz, 1H) 7.42 (d, J=8.5 Hz,2H) 7.53 (t, J=8.0 Hz, 1H) 7.59-7.64 (m, 3H) 8.04 (s, 1H) 9.00 (s, 1H)9.13 (s, 1H) MS (ESI(+)) m/e 427.0 (M+H)⁺.

Example 302N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting Example 297B and1-isocyanato-3,5-dimethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.24 (s, 6H) 2.45 (s, 3H) 5.20 (s, 2H) 6.63 (s, 1H)7.04 (d, J=7.5 Hz, 1H) 7.09 (s, 2H) 7.38 (dd, J=7.3, 0.9 Hz, 1H) 7.40(d, J=8.5 Hz, 2H) 7.60 (d, J=8.5 Hz, 2H) 8.56 (s, 1H) 8.81 (s, 1H) MS(ESI(+)) m/e 387.1 (M+H)⁺.

Example 303N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-ethylphenyl)urea

The desired product was prepared by substituting Example 297B and3-ethyl-1-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 1.19 (t, J=7.5 Hz, 3H) 2.45 (s, 3H) 2.58 (q, J=7.6Hz, 2H) 5.20 (s, 2H) 6.84 (d, J=7.5 Hz, 1H) 7.04 (d, J=7.5 Hz, 1H) 7.19(t, J=7.8 Hz, 1H) 7.27 (ddd, J=8.1, 2.0, 1.4 Hz, 1H) 7.33-7.35 (m, 1H)7.38 (dd, J=7.3, 0.9 Hz, 1H) 7.40 (d, J=8.5 Hz, 2H) 7.61 (d, J=8.5 Hz,2H) 8.66 (s, 1H) 8.82 (s, 1H) MS (ESI(+)) m/e 387.1 (M+H)⁺.

Example 304N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(4-methylphenyl)urea

The desired product was prepared by substituting Example 297B and1-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.25 (s, 3H) 2.45 (s, 3H) 5.19 (s, 2H) 7.03 (d,J=7.5 Hz, 1H) 7.10 (d, J=8.5 Hz, 2H) 7.34-7.41 (m, 5H) 7.60 (d, J=8.5Hz, 2H) 8.61 (s, 1H) 8.80 (s, 1H) MS (ESI(+)) m/e 373.1 (M+H)⁺.

Example 305N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-(trifluoromethoxy)phenyl]urea

The desired product was prepared by substituting Example 297B and1-trifluoromethoxy-4-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J=7.5 Hz, 1H)7.30 (d, J=8.5 Hz, 2H) 7.37-7.42 (m, 3H) 7.57-7.63 (m, 4H) 8.91 (s, 1H)8.95 (s, 1H) MS (ESI(+)) m/e 443.0 (M+H)⁺.

Example 306N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea

The desired product was prepared by substituting Example 297B and1-fluoro-5-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.17 (s, 3H) 2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d,J=7.5 Hz, 1H) 7.05 (dd, J=8.1, 2.0 Hz, 1H) 7.18 (t, J=8.7 Hz, 1H)7.37-7.39 (m, 1H) 7.41 (d, J=8.5 Hz, 2H) 7.46 (dd, J=12.6, 2.0 Hz, 1H)7.60 (d, J=8.5 Hz, 2H) 8.84 (s, 1H) 8.88 (s, 1H) MS (ESI(+)) m/e 391.1(M+H)⁺.

Example 307N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methoxyphenyl)urea

The desired product was prepared by substituting Example 297B and1-methoxy-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 3.74 (s, 3H) 5.20 (s, 2H) 6.57 (dd,J=8.1, 2.4 Hz, 1H) 6.95 (dd, J=7.6, 1.5 Hz, 1H) 7.04 (d, J=7.5 Hz, 1H)7.16-7.22 (m, 2H) 7.37-7.43 (m, 3H) 7.61 (d, J=8.5 Hz, 2H) 8.74 (s, 1H)8.84 (s, 1H) MS (ESI(+)) m/e 389.0 (M+H)⁺.

Example 308N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 297B andisocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene,respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.45 (s,3H) 5.20 (s, 2H) 6.98 (tt, J=7.1, 1.4 Hz, 1H) 7.04 (d, J=7.5 Hz, 1H)7.27-7.32 (m, 2H) 7.38 (dd, J=7.5, 1.0 Hz, 1H) 7.40 (d, J=8.8 Hz, 2H)7.48 (dd, J=8.8, 1.0 Hz, 2H) 7.61 (d, J=8.8 Hz, 2H) 8.72 (s, 1H) 8.85(s, 1H) MS (ESI(+)) m/e 359.0 (M+H)⁺.

Example 309N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-[3,5-bis(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 297B and1-isocyanato-3,5-bis(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.05 (d, J=7.1 Hz, 1H)7.39 (dd, J=7.5, 0.7 Hz, 1H) 7.43 (d, J=8.5 Hz, 2H) 7.63-7.66 (m, 3H)8.16 (s, 2H) 9.18 (s, 1H) 9.45 (s, 1H) MS (ESI(+)) m/e 495.0 (M+H)⁺.

Example 310N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 297B and1-bromo-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J=7.1 Hz, 1H)7.16 (ddd, J=7.8, 1.9, 1.2 Hz, 1H) 7.25 (t, J=8.0 Hz, 1H) 7.33 (ddd,J=8.0, 2.0, 1.2 Hz, 1H) 7.38 (m, J=7.5, 1.0 Hz, 1H) 7.41 (d, J=8.5 Hz,2H) 7.61 (d, J=8.5 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H) 8.93 (app. s., 2H) MS(ESI(+)) m/e 436.9, 438.9 (M+H)⁺.

Example 311N-[4-(3-amino-7-methyl-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea

The desired product was prepared by substituting Example 297B forExample 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.45 (s, 3H)5.19 (s, 2H) 6.80 (tdd, J=8.5, 2.7, 1.0 Hz, 1H) 7.04 (d, J=7.5 Hz, 1H)7.14 (ddd, J=8.2, 2.0, 0.7 Hz, 1H) 7.32 (td, J=8.2, 7.0 Hz, 1H)7.37-7.44 (m, 3H) 7.51 (dt, J=12.0, 2.3 Hz, 1H) 7.61 (d, J=8.5 Hz, 2H)8.92 (s, 1H) 8.96 (s, 1H) MS (ESI(+)) m/e 377.1 (M+H)⁺.

Example 312N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 100C and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 7.05 (d, J=8.1 Hz, 1H)7.16 (d, J=8.1 Hz, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.45 (t, J=9.8 Hz, 1H)7.61 (d, J=8.5 Hz, 2H) 7.64-7.69 (m, 1H) 8.02 (dd, J=6.4, 2.7 Hz, 1H)8.97 (s, 1H) 9.09 (s, 1H) MS (ESI(+)) m/e 461.0 (M+H)⁺.

Example 313N-[4-(3-amino-7-methoxy-1,2-benzisoxazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 100C and1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.22 (d, J=2.0 Hz, 3H) 3.96 (s, 3H) 5.20 (s, 2H)7.03-7.09 (m, 2H) 7.16 (d, J=8.1 Hz, 1H) 7.27 (ddd, J=8.5, 4.1, 3.0 Hz,1H) 7.35-7.39 (m, 3H) 7.59 (d, J=8.5 Hz, 2H) 8.66 (s, 1H) 8.81 (s, 1H)MS (ESI(+)) m/e 407.1 (M+H)⁺.

Example 314N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]ureaExample 314A 7-fluoro-4-iodo-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 26A for2-bromo-6-fluorobenzonitrile in Example 95A. MS (ESI(+)) m/e 278.8(M+H)⁺.

Example 314B 4-(4-aminophenyl)-7-fluoro-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 314A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for Examples 1Aand 1B, respectively, in Example 1C. MS (ESI(+)) m/e 244.0 (M+H)⁺.

Example 314CN-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 314B and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.38 (s, 2H) 7.12 (dd, J=8.3, 3.9 Hz, 1H) 7.33 (d,J=7.8 Hz, 1H) 7.43 (d, J=8.8 Hz, 2H) 7.52 (dd, J=10.9, 8.1 Hz, 1H) 7.53(t, J=7.8 Hz, 1H) 7.59-7.65 (m, 3H) 8.04 (s, 1H) 9.00 (s, 1H) 9.12 (s,1H) MS (ESI(+)) m/e 431.0 (M+H)⁺.

Example 315N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 314B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.38 (s, 2H) 7.03 (dt, J=6.4, 2.2 Hz, 1H) 7.12 (dd,J=8.1, 4.1 Hz, 1H) 7.27-7.35 (m, 2H) 7.42 (d, J=8.5 Hz, 2H) 7.52 (dd,J=10.9, 8.1 Hz, 1H) 7.62 (d, J=8.5 Hz, 2H) 7.72-7.74 (m, 1H) 8.95 (s,1H) 8.96 (s, 1H) MS (ESI(+)) m/e 397.0 (M+H)⁺.

Example 316N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 314B and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.37 (s, 2H) 7.12 (dd, J=8.1, 4.1 Hz, 1H) 7.43 (d,J=8.5 Hz, 2H) 7.43 (d, J=9.2 Hz, 1H) 7.52 (dd, J=10.9, 8.1 Hz, 1H) 7.63(d, J=8.5 Hz, 2H) 7.64-7.69 (m, 1H) 8.02 (dd, J=6.4, 2.7 Hz, 1H) 9.01(s, 1H) 9.10 (s, 1H) MS (ESI(+)) m/e 449.0 (M+H)⁺.

Example 317N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 314B and1-isocyanato-3-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.29 (s, 3H) 5.38 (s, 2H) 6.81 (d, J=7.5 Hz, 1H)7.11 (dd, J=8.1, 4.1 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz,1H) 7.32 (s, 1H) 7.41 (d, J=8.5 Hz, 2H) 7.51 (dd, J=10.9, 8.1 Hz, 1H)7.62 (d, J=8.5 Hz, 2H) 8.65 (s, 1H) 8.85 (s, 1H) MS (ESI(+)) m/e 377.1(M+H)⁺.

Example 318N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 314B and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.38 (s, 2H) 7.12 (dd, J=8.3, 3.9 Hz, 1H) 7.38-7.55(m, 5H) 7.64 (d, J=8.8 Hz, 2H) 8.64 (dd, J=7.3, 2.2 Hz, 1H) 8.97 (d,J=3.1 Hz, 1H) 9.37 (s, 1H) MS (ESI(+)) m/e 449.0 (M+H)⁺.

Example 319N-[4-(3-amino-7-fluoro-1,2-benzisoxazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 314B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.28 (s, 3H) 5.38 (s, 2H) 6.79-6.84 (m, 1H)7.08-7.15 (m, 2H) 7.43 (d, J=8.5 Hz, 2H) 7.52 (dd, J=10.9, 8.1 Hz, 1H)7.62 (d, J=8.5 Hz, 2H) 8.00 (dd, J=7.6, 1.9 Hz, 1H) 8.55 (d, J=2.4 Hz,1H) 9.25 (s, 1H) MS (ESI(+)) m/e 395.0 (M+H)⁺.

Example 320N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureaExample 320A 6-bromo-2-fluoro-3-(trifluoromethoxy)benzonitrile

The desired product was prepared by substituting4-bromo-2-fluoro-1-trifluoromethoxy-benzene for2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C. MS (ESI(−)) m/e 282(M−H)⁻.

Example 320B 4-bromo-7-(trifluoromethoxy)-1,2-benzisoxazol-3-amine

A solution of propan-2-one oxime (810 mg, 1.1 mmol) in THF (50 mL) wastreated with potassium tert-butoxide (1.23 g) stirred at r.t for 30 min,then treated with example 320A (2.84 g, 10 mmol). The reaction mixturewas stirred at r.t. for 30 min, then partitioned between EtOAc andwater. The organic extract was washed with brine, dried (MgSO₄) andconcentrated. The residue was dissolved in ethanol (20 mL), treated with5% HCl (20 mL) and heated at reflux for 2 h. The reaction was allowed tocool to r.t the concentrated to half its volume resulting in aprecipitate which was collected via filtration. The crude solid waspurified via silica gel chromatography eluting with 0 to 10%EtOAc-hexanes to give 0.95 g of example 320B. MS (ESI(+)) m/e 297, 299(M+H)⁺.

Example 320C4-(4-aminophenyl)-7-(trifluoromethoxy)-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 320B forExample 15H in Example 15G. MS (ESI(+)) m/e 310 (M+H)⁺.

Example 320DN-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 320C and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.44 (s, 2H), 7.22 (d, J=7.80 Hz, 1H), 7.35-7.46 (m,1H), 7.46-7.52 (m, 3H), 7.62-7.72 (m, 3H), 8.64 (dd, J=7.29, 2.20 Hz,1H), 8.98 (d, J=2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI(+)) m/e 515 (M+H)⁺.

Example 321N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 320C and1-isocyanato-3-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.44 (s, 2H), 7.22 (d, J=8.14 Hz, 1H), 7.33 (d,J=7.80 Hz, 1H), 7.45-7.72 (m, 7H), 8.04 (s, 1H), 9.03 (s, 1H), 9.13 (s,1H); MS (ESI(+)) m/e 497 (M+H)⁺.

Example 322N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 320C and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.28 (s, 3H), 5.44 (s, 2H), 6.75-6.90 (m, 1H), 7.12(dd, J=11.36, 8.31 Hz, 1H), 7.21 (d, J=8.14 Hz, 1H), 7.47 (d, J=8.82 Hz,2H), 7.55-7.75 (m, 3H), 8.00 (dd, J=7.97, 1.86 Hz, 1H), 8.56 (d, J=2.71Hz, 1H), 9.28 (s, 1H); MS (ESI(+)) m/e 461 (M+H)⁺.

Example 323N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 320C and3-chloro-1-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.43 (s, 2H), 7.95-7.06 (m, 1H), 7.21 (d, J=8.14 Hz,1H), 7.25-7.35 (m, 2H), 7.47 (d, J=8.48 Hz, 2H), 7.6-7.9 (m, 4H), 8.97(s, 1H), 8.99 (s, 1H); MS (ESI(+)) m/e 463 (M+H)⁺.

Example 324N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-(3-bromophenyl)urea

The desired product was prepared by substituting Example 320C and3-bromo-1-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.43 (s, 2H), 7.10-7.37 (m, 4H), 7.47 (d, J=8.82 Hz,2H), 7.60-7.72 (m, 3H), 7.88 (t, J=2.03 Hz, 1H), 8.96 (s, 1H), 8.99 (s,1H); MS (ESI(+)) m/e 507 (M+H)⁺.

Example 325N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 320C and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 5.43 (s, 2H), 7.21 (d, J=8.14 Hz, 1H), 7.40-7.52 (m,J=9.15, 9.15 Hz, 3H), 7.60-7.75 (m, 4H), 7.90-8.10 (dd, J=6.44, 2.71 Hz,1H), 9.04 (s, 1H), 9.12 (s, 1H); MS (ESI(+)) m/e 515 (M+H)⁺.

Example 326N-{4-[3-amino-7-(trifluoromethoxy)-1,2-benzisoxazol-4-yl]phenyl}-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 320C and1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) δ ppm 2.23 (s, 3H), 5.43 (s, 2H), 7.06 (t, J=9.16 Hz, 1H),7.21 (d, J=8.14 Hz, 1H), 7.25-7.40 (m, 2H), 7.45 (d, J=8.48 Hz, 2H),7.58-7.78 (m, 3H), 8.69 (s, 1H), 8.88 (s, 1H); MS (ESI(+)) m/e 461(M+H)⁺.

Example 327N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)ureaExample 327A 2-(benzylthio)-6-iodobenzonitrile

A suspension of potassium tert-butoxide (1.12 g, 10.0 mmol) andphenyl-methanethiol (1.24 g, 10 mmol) in THF (30 mL) at room temperaturewas stirred for 10 minutes before treating with2-fluoro-6-iodo-benzonitrile (2.47 g, 10 mmol). The solution was stirredfor 1 hour at room temperature, poured into a saturated ammoniumchloride solution and filtered. The filter cake was recrystallized fromhexanes to provide 2.41 g (53% yield) of the desired product. MS(ESI(−)) m/e 350.0 (M−H)⁻.

Example 327B 4-iodo-1,2-benzisothiazol-3-amine

Example 327A (2.5 g, 7.1 mmol) was treated with sulfuryl chloride (1.0 Min dichloromethane, 3.5 mL, 35.5 mmol), stirred at room temperature for2 hours and concentrated. The residue was dissolved in minimal THF,treated with ammonia (7.0 M in methanol, 10 mL), stirred at roomtemperature for 1 hour, diluted with water and extracted with ethylacetate. The combine organic layers were washed with brine, dried(MgSO₄), filtered and concentrated. The residue was triturated fromethyl acetate/hexanes to provide 1.2 g (61% yield) of the desiredproduct. MS (ESI(−)) m/e 274.8, 276.7 (M−H)⁻.

Example 327CN-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N′-(3,5-dimethylphenyl)urea

The desired product was prepared by substituting1-isocyanato-3,5-dimethylbenzene for 1-isocyanato-3-methylbenzene, inexample 1B and Example 327B for example 1A in example 1C. In additionPdCl₂.dppf.CH₂Cl₂ was used in place of Pd(PPh₃)₄. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 2.24 (s, 6H), 5.45 (s, 2H), 6.63 (s, 1H), 7.09 (s, 2H),7.35 (d, J=8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.97 (d, J=8.14 Hz, 1H),8.59 (s, 1H), 8.85 (s, 2H); MS (ESI(+)) m/e 389.0 (M+H)⁺.

Example 328N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting3-chloro-1-isocyanatobenzene for 1-isocyanato-3-methylbenzene, inexample 1B and Example 327B for example 1A in example 1C. In additionPdCl₂.dppf.CH₂Cl₂ was used in place of Pd(PPh₃)₄. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 5.45 (s, 2H), 7.01-7.10 (m, 1H), 7.17 (d, J=7.80 Hz, 1H),7.30-7.40 (m, 3H), 7.50-7.65 (m, 4H), 7.70-7.80 (m, 1H), 7.97 (dd,J=7.97, 0.85 Hz, 1H), 9.00 (s, 2H); MS (ESI(+)) m/e 395.0 (M+H)⁺.

Example 329N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting1-fluoro-2-isocyanato-4-methylbenzen for 1-isocyanato-3-methylbenzene,in example 1B and Example 327B for example 1A in example 1C. In additionPdCl₂.dppf.CH₂Cl₂ was used in place of Pd(PPh₃)₄. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 2.28 (s, 3H), 5.45 (s, 2H) 6.78-6.88 (m, 1H) 7.05-7.25(m, 2H), 7.37 (d, J=8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.90-8.10 (m, 2H),8.56 (d, J=2.37 Hz, 1H), 9.28 (s, 1H); MS (ESI(+)) m/e 393.0 (M+H)⁺.

Example 330N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 327B forexample 1A in example 1C. In addition PdCl₂.dppf.CH₂Cl₂ was used inplace of Pd(PPh₃)₄. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.29 (s, 3H), 5.45(s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.20-7.40 (m, 3H), 7.48-7.56 (m, 6H),7.97 (d, J=8.14 Hz, 1H), 8.67 (s, 1H), 8.87 (s, 1H); MS (ESI(+)) m/e375.0 (M+H)⁺.

Example 331N-[4-(3-amino-1,2-benzisothiazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-(trifluoromethyl)benzene for1-isocyanato-3-methylbenzene, in example 1B and Example 327B for example1A in example 1C. In addition PdCl₂.dppf.CH₂Cl₂ was used in place ofPd(PPh₃)₄. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.45 (s, 2H), 7.17 (d, J=7.12Hz, 1H), 7.25-7.45 (m, 3H), 7.50-7.60 (m, 5H), 7.97 (d, J=7.46 Hz, 1H),8.04 (s, 1H), 9.02 (s, 1H), 9.14 (s, 1H); MS (ESI(+)) m/e 429 (M+H)⁺.

Example 332N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 332A2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine

The desired product was prepared by substituting4-bromo-2-fluoro-phenylamine for Example 149A in Example 149B. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 3.32 (s, 12H) 5.56 (s, 2H) 6.72 (dd, J=8.82,7.80 Hz, 1H) 7.13 (m, 1H) 7.18 (dd, J=7.97, 1.19 Hz, 1H).

Example 332BN-(2-fluoro-5-methylphenyl)-N′-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

The desired product was prepared by substituting Example 332A for4-bromo-2-ethylaniline in Example 149A. MS (ESI(+)) m/e 389 (M+H)⁺.

Example 332C 7-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting Example 26A for Example15E in Example 15F. MS (ESI(+)) m/e 278 (M+H)⁺.

Example 332DN-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 332B andExample 332C for Example 1B and Example 1A, respectively, in Example 1C.¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.28 (s, 3H), 6.77-6.81 (m, 2H),7.09-7.17 (m, 2H), 7.24 (dd, J=8.48, 2.03 Hz, 1H), 7.36 (dd, J=12.21,2.03 Hz, 1H), 8.03 (dd, J=7.97, 2.20 Hz, 1H), 8.31 (t, J=8.48 Hz, 1H),9.03 (d, J=2.37 Hz, 1H), 9.15 (d, J=2.37 Hz, 1H); MS (ESI(+) m/e 412(M+H)⁺.

Example 333N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chlorophenyl)ureaExample 333AN-(3-chlorophenyl)-N′-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

The desired product was prepared by substituting Example 332A and1-chloro-3-isocyanato-benzene for 4-bromo-2-ethylaniline and1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 149A. MS(ESI(+)) m/e 391 (M+H)⁺.

Example 333BN-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 333A andExample 332C for Example 1B and Example 1A, respectively, in Example 1C.¹H NMR (300 MHz, DMSO-D₆) δ ppm 6.79 (dd, J=7.80, 4.07 Hz, 1H),7.03-7.07 (m, 1H), 7.14 (dd, J=11.36, 7.97 Hz, 1H), 7.24-7.39 (m, 4H),7.75 (t, J=2.03 Hz, 1H), 8.25 (t, J=8.48 Hz, 1H), 8.73 (d, J=2.37 Hz,1H), 9.31 (s, 1H); MS (ESI(+) m/e 414 (M+H)⁺.

Example 334N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)ureaExample 334A2-fluoro-6-iodo-3-[(1-methylpiperidin-4-yl)methoxy]benzonitrile

The desired product was prepared by substituting1-methyl-4-piperidinemethanol for 2-(4-morpholinyl)ethanol in Example75A. MS (ESI(+)) m/e 375 (M+H)⁺.

Example 334B4-iodo-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-3-amine

The desired product was prepared by substituting Example 334A forExample 15E in Example 15F. MS (ESI(+)) m/e 387 (M+H)⁺.

Example 334CN-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 334B andExample 5A for Example 1A and Example 1B in Example 1C. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 1.42-1.58 (m, 2H), 2.08-2.18 (m, 3H), 2.28 (s, 3H), 2.79(d, J=4.75 Hz, 3H), 2.91-3.11 (m, 2H), 3.51 (d, J=12.21 Hz, 2H), 4.03(d, J=6.44 Hz, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.81-6.83 (m, 2H), 7.11(dd, J=11.36, 8.31 Hz, 1H), 7.36 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.81 Hz,2H), 8.00 (dd, J=7.97, 2.20 Hz, 1H), 8.53 (d, J=2.71 Hz, 1H), 9.19 (s,1H); MS (ESI(+) m/e 503 (M+H)⁺.

Example 335N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 334B forExample 1A in Example 1C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 1.41-1.53 (m,2H), 2.07-2.18 (m, 3H), 2.29 (s, 3H), 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05(m, 2H), 3.51 (d, J=12.55 Hz, 2H), 4.03 (d, J=6.44 Hz, 2H), 6.71 (d,J=7.46 Hz, 1H), 6.81 (m, 2H), 7.16 (m, 1H), 7.25 (d, J=8.14 Hz, 1H),7.32 (s, 1H), 7.34 (d, J=8.48 Hz, 2H), 7.57 (d, J=8.48 Hz, 2H), 8.69 (s,1H), 8.83 (s, 1H); MS (ESI(+) m/e 485 (M+H)⁺.

Example 336N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 334B and1-chloro-3-isocyanatobenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 1.41-1.53 (m, 2H), 2.07-2.18 (m, 3H), 2.79 (d,J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J=12.55 Hz, 2H), 4.03 (d,J=6.44 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.82 (d, J=7.80 Hz, 1H),7.01-7.04 (m, 1H), 7.30-7.32 (m, 2H), 7.36 (d, J=8.48 Hz, 2H), 7.57 (d,J=8.48 Hz, 2H), 7.74 (m, 1H), 8.98 (s, 1H), 9.04 (s, 1H); MS (ESI(+) m/e505 (M+H)⁺.

Example 337N-(4-{3-amino-7-[(1-methylpiperidin-4-yl)methoxy]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 334B and1-fluoro-2-methyl-4-isocyanatobenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 1.41-1.53 (m, 2H), 2.07-2.18 (m, 3H), 2.22 (s,3H) 2.79 (d, J=4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J=12.55 Hz,2H), 4.03 (d, J=6.44 Hz, 2H), 6.72 (d, J=7.46 Hz, 1H), 6.82 (d, J=7.80Hz, 1H), 7.05 (t, J=9.16 Hz, 1H), 7.25-7.40 (m, 2H), 7.34 (d, J=8.48 Hz,2H), 7.56 (d, J=8.82 Hz, 2H), 8.73 (s, 1H), 8.85 (s, 1H); MS (ESI(+) m/e503 (M+H)⁺.

Example 338N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)ureaExample 338A 2-fluoro-6-iodo-3-(3-pyridin-3-ylpropoxy)benzonitrile

The desired product was prepared by 3-pyridinepropanol for2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+)) m/e 383 (M+H)⁺.

Example 338B 4-iodo-7-(3-pyridin-3-ylpropoxy)-1H-indazol-3-amine

The desired product was prepared by substituting Example 338A forExample 15E in Example 15F. MS (ESI(+)) m/e 395 (M+H)⁺.

Example 338CN-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 338B and1-chloro-3-isocyanatobenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J=7.12 Hz, 2H),4.16 (t, J=5.93 Hz, 2H), 6.73 (d, J=7.80 Hz, 1H), 6.81 (d, J=7.80 Hz,1H), 7.01-7.04 (m, 1H), 7.27-7.32 (m, 2H), 7.37 (d, J=8.81 Hz, 2H), 7.58(d, J=8.81 Hz, 2H), 7.74 (t, J=2.03 Hz, 1H), 7.83 (dd, J=7.80, 5.42 Hz,1H), 8.32 (d, J=7.80 Hz, 1H), 8.69 (d, J=4.07 Hz, 1H), 8.77 (d, J=2.03Hz, 1H), 8.97 (s, 1H), 9.03 (s, 1H); MS (ESI(+) m/e 513 (M+H)⁺.

Example 339N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 338B forExample 1A in Example 1C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.15-2.22 (m,2H), 2.29 (s, 3H), 3.05 (t, J=7.12 Hz, 2H), 4.16 (t, J=5.93 Hz, 2H),6.72 (d, J=7.80 Hz, 1H), 6.79-6.82 (m, 2H), 7.16 (m, 1H), 7.25 (m, 1H),7.32 (s, 1H), 7.35 (d, J=8.81 Hz, 2H), 7.57 (d, J=8.81 Hz, 2H), 7.83(dd, J=7.80, 5.42 Hz, 1H), 8.31 (d, J=8.14 Hz, 1H), 8.69 (m, 2H), 8.77(d, J=1.69 Hz, 1H), 8.82 (s, 1H); MS (ESI(+) m/e 493 (M+H)⁺.

Example 340N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 338B and1-fluoro-4-isocyanato)-2-(trifluoromethyl)benzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.07-2.19 (m, 2H), 3.05 (t, J=7.12 Hz, 2H),4.15 (t, J=5.93 Hz, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz,1H), 7.37 (d, J=8.82 Hz, 2H), 7.45 (t, J=9.16 Hz, 1H), 7.58 (d, J=8.48Hz, 2H), 7.66 (m, 1H), 7.78 (dd, J=7.80, 5.42 Hz, 1H), 8.04 (dd, J=6.78,2.71 Hz, 1H), 8.25 (d, J=8.14 Hz, 1H), 8.66 (d, J=4.41 Hz, 1H), 8.74 (d,J=1.70 Hz, 1H), 9.00 (s, 1H), 9.16 (s, 1H); MS (ESI(+) m/e 565 (M+H)⁺.

Example 341N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 338B and1-fluoro-4-isocyanato-2-methylbenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.15-2.22 (m, 2H), 2.22 (s, 3H), 3.05 (t,J=7.12 Hz, 2H), 4.15 (t, J=6.10 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.82(d, J=7.80 Hz, 1H), 7.05 (t, J=9.16 Hz, 1H), 7.19-7.40 (m, 4H), 7.56 (d,J=8.48 Hz, 2H), 7.82 (dd, J=7.97, 5.26 Hz, 1H), 8.30 (d, J=7.12 Hz, 1H),8.69 (dd, J=5.43, 1.36 Hz, 1H), 8.73 (s, 1H), 8.76 (d, J=1.70 Hz, 1H),8.85 (s, 1H); MS (ESI(+) m/e 511 (M+H)⁺.

Example 342N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chloro-4-fluorophenyl)urea

The desired product was prepared by substituting Example 338B and1-fluoro-2-chloro-4-isocyanatobenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J=7.12 Hz, 2H),4.15 (t, J=5.93 Hz, 2H), 6.71 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.80 Hz,1H), 7.33-7.38 (m, 4H), 7.57 (d, J=8.48 Hz, 2H), 7.77-7.84 (m, 2H), 8.27(d, J=7.80 Hz, 1H), 8.67 (dd, J=5.42, 1.36 Hz, 1H), 8.75 (d, J=1.70 Hz,1H), 8.97 (s, 1H), 9.01 (s, 1H); MS (ESI(+) m/e 531 (M+H)⁺.

Example 343N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 338B and1-isocyanato-3-(trifluoromethyl)benzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J=7.12 Hz, 2H),4.15 (t, J=6.10 Hz, 2H), 6.72 (d, J=7.80 Hz, 1H), 6.81 (m, 1H), 7.32 (d,J=7.46 Hz, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.53 (t, J=7.97 Hz, 1H), 7.60(m, 3H), 7.81 (dd, J=8.14, 5.42 Hz, 1H), 8.05 (s, 1H), 8.28 (d, J=8.14Hz, 1H), 8.68 (dd, J=5.26, 1.19 Hz, 1H), 8.76 (d, J=1.70 Hz, 1H), 9.01(s, 1H), 9.19 (s, 1H); MS (ESI(+) m/e 547 (M+H)⁺.

Example 344N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)ureaExample 344A 2-fluoro-6-iodo-3-(3-pyridin-4-ylpropoxy)benzonitrile

The desired product was prepared by 4-pyridinepropanol for2-(4-morpholinyl)ethanol in Example 75A. MS (ESI(+) m/e 382.9 (M+H)⁺.

Example 344B 4-iodo-7-(3-pyridin-4-ylpropoxy)-1H-indazol-3-amine

The desired product was prepared by substituting Example 344A forExample 15E in Example 15F. MS (ESI(+) m/e 395 (M+H)⁺.

Example 344CN-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 344B and1-fluoro-2-isocyanato-4-methylbenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.09-2.15 (m, 2H), 2.28 (s, 3H), 2.90 (t,J=7.12 Hz, 2H), 4.13 (t, J=6.10 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J=7.80Hz, 1H), 6.75 (d, J=7.80 Hz, 1H), 6.78-6.82 (m, 1H), 7.11 (dd, J=11.36,8.31 Hz, 1H), 7.31 (d, J=6.10 Hz, 2H), 7.36 (d, J=8.48 Hz, 2H), 7.56 (d,J=8.48 Hz, 2H), 8.01 (dd, J=7.97, 2.20 Hz, 1H), 8.47 (d, J=5.76 Hz, 2H),8.53 (d, J=2.71 Hz, 1H), 9.18 (s, 1H), 11.90 (s, 1H); MS (ESI(+) m/e 511(M+H)⁺.

Example 345N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 344B forExample 1A in Example 1C. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.07-2.16 (m,2H), 2.29 (s, 3H), 2.90 (m, 2H), 4.13 (t, J=5.93 Hz, 2H), 4.32 (s, 2H),6.67 (d, J=7.46 Hz, 1H), 6.75 (d, J=7.80 Hz, 1H), 6.80 (d, J=7.12 Hz,1H), 7.16 (t, J=7.80 Hz, 1H), 7.25 (d, J=8.14 Hz, 1H), 7.31 (dd, J=4.07,1.70 Hz, 3H), 7.35 (d, J=8.48 Hz, 2H), 7.56 (d, J=8.48 Hz, 2H), 8.47 (d,J=6.10 Hz, 2H), 8.64 (s, 1H), 8.77 (s, 1H), 11.90 (s, 1H); MS (ESI(+)m/e 493 (M+H)⁺.

Example 346N-{4-[3-amino-7-(3-pyridin-4-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 344B and1-chloro-3-isocyanatobenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. ¹H NMR(300 MHz, DMSO-D₆) δ ppm 2.13 (m, 2H), 4.13 (t, J=6.10 Hz, 2H), 4.32 (s,2H), 6.67 (d, J=7.80 Hz, 1H), 6.75 (m, 1H), 7.02 (m, 1H), 7.31 (m,J=6.10, 2.03 Hz, 5H), 7.36 (d, J=8.81 Hz, 2H), 7.56 (m, J=8.48 Hz, 3H),7.73 (s, 1H), 8.47 (m, 2H), 8.90 (s, 1H), 8.97 (s, 1H), 11.90 (s, 1H);MS (ESI(+) m/e 513 (M+H)⁺.

Example 347N-[4-(3-amino-1H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 347AN-(4-bromo-2-hydroxyphenyl)-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting 2-Amino-5-bromo-phenolfor 4-bromo-2-ethylaniline in example 149A. MS (ESI(+)) m/e 339 and 341(M+H)⁺.

Example 347BN-[4-bromo-2-(methoxymethoxy)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

A solution of example 347A (68 mg, 0.2 mmol) in acetone (2 mL) wastreated with K2CO3 (41 mg, 0.3 mmol) and MOM-Cl (0.023 mL, 0.3 mmol),stirred at reflux for 2 h, then allowed to cool to room temperature andtreated with water. The resulting suspension was filtered and the filtercake was dried to give 58 mg of example 347B. ¹H NMR (300 MHz, DMSO-D₆)δ ppm 2.27 (s, 3H) 3.45 (s, 3H) 5.32 (s, 2H) 6.78-6.83 (m, 1H) 7.12-7.15(m, 2H) 7.29 (d, J=2.37 Hz, 1H) 7.98 (dd, J=7.97, 1.86 Hz, 1H) 8.13 (d,J=8.82 Hz, 1H) 8.82 (s, 1H) 9.22 (d, J=1.70 Hz, 1H).

Example 347CN-[4-(3-amino-1H-indazol-4-yl)-2-(methoxymethoxy)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared substituting example 347B for example44A in example 44B. ¹H NMR (300 MHz, DMSO-D₆) d ppm 2.28 (s, 3H) 3.47(s, 3H) 4.42 (s, 2H) 5.37 (s, 2H) 6.78-6.83 (m, 2H) 7.08 (dd, J=8.3, 1.9Hz, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.24 (d, J=2.0 Hz, 1H) 7.26 (s,1H) 7.27 (d, J=2.7 Hz, 1H) 8.04 (dd, J=8.1, 2.0 Hz, 1H) 8.29 (d, J=8.5Hz, 1H) 8.89 (s, 1H) 9.26 (d, J=1.7 Hz, 1H) 11.72 (s, 1H); MS (ESI(+))m/e 436.2 (M+H)⁺.

Example 348N-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 348AN-(4-bromo-2-tetrahydro-2H-pyran-2-ylphenyl)-N′-(2-fluoro-5-methylphenyl)urea

A solution of example 347A (150 mg, 0.44 mmol) and dihydropyran (0.24mL, 2.4 mmol) in CH₂Cl₂ (2 mL) was treated with TsOH (1 mg) stirred atroom temperature for 1 h then partitioned between EtOAc and sat. aq.NaHCO₃ solution. The organic extract was washed with brine, dried(MgSO₄), concentrated and purified via silica gel chromatography elutingwith 20% EtOAc-hexanes to give 190 mg of 348A.

Example 348BN-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting example 348A (190 mg,0.4 mmol) for 44A in example 44B, then dissolving the crude product inmethanol treating with one drop of 1N HCl and stirring at r.t for 12 h.Purification via silica gel chromatography eluting with 5%methanol-methylene chloride gave 14 mg of 348B. ¹H NMR (500 MHz,DMSO-D₆) d ppm 2.28 (s, 3H) 6.77-6.81 (m, 2H) 6.85 (dd, J=8.4, 1.9 Hz,1H) 6.94 (d, J=2.2 Hz, 1H) 7.09 (dd, J=11.2, 8.4 Hz, 1H) 7.24-7.29 (m,2H) 8.02 (dd, J=7.8, 1.3 Hz, 1H) 8.17 (d, J=8.4 Hz, 1H) 8.81 (s, 1H)9.19 (d, J=1.9 Hz, 1H) 10.14 (s, 1H) 11.74 (s, 1H); MS (ESI(+)) m/e391.7 (M+H)⁺.

Example 349N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(hydroxymethyl)phenyl]ureaExample 349A N-(4-bromophenyl)-N′-[2-fluoro-5-(hydroxymethyl)phenyl]urea

A solution of (3-amino-4-fluoro-phenyl)-methanol (0.61 g, 4.3 mmol) inCH₂Cl₂ (20 mL) was treated with 1-isocyanato-4-bromobenzene (0.85 g, 4.3mmol) stirred at room temperature overnight resulting in a thicksuspension which was filtered to give 1.43 g of 349 as a off whitesolid. MS (ESI(−)) m/e 336.9, 338.9 (M−H)⁺.

Example 349BN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(hydroxymethyl)phenyl]urea

The desired product was prepared by substituting example 349A for 149Ain examples 149B-C. ¹H NMR (300 MHz, DMSO-D₆) d ppm 4.33 (s, 2H) 4.46(d, J=5.8 Hz, 2H) 5.22 (t, J=5.8 Hz, 1H) 6.79 (dd, J=5.4, 2.4 Hz, 1H)6.95 (ddd, J=8.1, 4.8, 2.0 Hz, 1H) 7.11-7.30 (m, 3H) 7.41 (d, J=8.5 Hz,2H) 7.60 (d, J=8.5 Hz, 2H) 8.16 (dd, J=7.8, 2.0 Hz, 1H) 8.58 (d, J=2.4Hz, 1H) 9.21 (s, 1H) 11.71 (s, 1H); MS (ESI(+)) m/e 392.0 (M+H)⁺.

Example 350N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]ureaExample 350A 4-(4-aminophenyl)-7-thien-3-yl-1H-indazol-3-amine

The desired product was prepared substituting thiophene-3-boronic acidfor pyridine-3-boronic acid in examples 243D-E, then following theprocedure of example 352B. R_(f)=0.24 (EtOAc).

Example 350BN-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 350A and1-isocyanato-3-trifluoromethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) d ppm 6.92 (d, J=7.1 Hz, 1H) 7.33 (d, J=7.5 Hz, 1H) 7.44(d, J=8.8 Hz, 2H) 7.48-7.68 (m, 6H) 7.73 (dd, J=4.8, 2.7 Hz, 1H) 7.96(d, J=2.4 Hz, 1H) 8.05 (s, 1H) 9.01 (s, 1H) 9.15 (s, 1H) 11.96 (s, 1H);MS (ESI(+)) m/e 494.0 (M+H)⁺.

Example 351N-[4-(3-amino-7-thien-3-yl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 350A and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300MHz, DMSO-D₆) d ppm 2.29 (s, 3H) 6.79-6.84 (m, 1H) 6.89 (d, J=7.5 Hz,1H) 7.12 (dd, J=11.4, 8.3 Hz, 1H) 7.44 (d, J=8.5 Hz, 2H) 7.54 (d, J=7.1Hz, 1H) 7.57-7.64 (m, 3H) 7.72 (dd, J=4.9, 2.9 Hz, 1H) 7.95 (s, 1H) 8.02(d, J=6.8 Hz, 1H) 8.55 (d, J=2.0 Hz, 1H) 9.23 (s, 1H) 11.84 (s, 1H); MS(ESI(+)) m/e 458.1 (M+H)⁺.

Example 352N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)ureaExample 352A 4-(4-nitrophenyl)-7-pyridin-4-yl-1H-indazol-3-amine

The desired product was prepared by substituting pyridine-4-boronic acidfor pyridine-3-boronic acid in examples 243D-E. Unlike example 243E onlya small amount (ca. 20%) of the reduced product 352A was obtained. MS(ESI(+)) m/e 332 (M+H)⁺.

Example 352B 4-(4-aminophenyl)-7-pyridin-4-yl-1H-indazol-3-amine

A mixture of 352A (370 mg, 1.1 mmol), iron (374 mg) and NH4Cl (60 mg,1.1 mmol) in ethanol (20 mL), THF (10 mL) and water (4 mL) was heated atreflux for 5 h, diluted with THF (20 mL), filtered through a pad ofcelite, washing with ethanol. The filtrate was concentrated and theresidue was triturated from water to give 313 mg of 352A as a lightyellow solid. MS (ESI(+)) m/e 302 (M+H)⁺.

Example 352CN-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting Example 352B and1-fluoro-4-isocyanato-2-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)d ppm 2.23 (d, J=2.0 Hz, 3H) 7.02 (d, J=7.5 Hz, 1H) 7.06 (t, J=9.2 Hz,1H) 7.29 (ddd, J=8.7, 4.3, 2.9 Hz, 1H) 7.39 (dd, J=7.1, 2.4 Hz, 1H) 7.46(d, J=8.8 Hz, 2H) 7.64 (d, J=8.8 Hz, 2H) 7.72 (d, J=7.5 Hz, 1H) 8.22 (d,J=3.7 Hz, 2H) 8.78 (s, 1H) 8.85-8.92 (m, 2H) 8.96 (s, 1H); MS (ESI(+))m/e 453.3 (M+H)⁺.

Example 353N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 352B and1-isocyanato-3-trifluoromethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)d ppm 7.02 (d, J=7.1 Hz, 1H) 7.33 (d, J=7.5 Hz, 1H) 7.48 (d, J=8.5 Hz,2H) 7.53 (t, J=8.0 Hz, 1H) 7.62 (d, J=8.5 Hz, 1H) 7.67 (d, J=8.5 Hz, 2H)7.71 (d, J=7.8 Hz, 1H) 8.05 (s, 1H) 8.19 (d, J=2.4 Hz, 2H) 8.87 (d,J=2.4 Hz, 2H) 9.11 (s, 1H) 9.23 (s, 1H); MS (ESI(+)) m/e 489.1 (M+H)⁺.

Example 354N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting Example 352B and1-chloro-3-isocyanatobenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)d ppm 7.00-7.05 (m, 2H) 7.29-7.33 (m, 2H) 7.47 (d, J=8.8 Hz, 2H) 7.65(d, J=8.8 Hz, 2H) 7.70 (d, J=7.5 Hz, 1H) 7.75 (dd, J=2.5, 1.2 Hz, 1H)8.17 (d, J=3.7 Hz, 2H) 8.86 (d, J=3.7 Hz, 2H) 9.08 (app. s, 2H); MS(ESI(+)) m/e 455.2 (M+H)⁺.

Example 355N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 352B and1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)d ppm 2.29 (s, 3H) 6.80-6.85 (m, 1H) 7.01 (d, J=7.5 Hz, 1H) 7.12 (dd,J=11.4, 8.3 Hz, 1H) 7.47 (d, J=8.8 Hz, 2H) 7.64 (d, J=8.8 Hz, 2H) 7.69(d, J=7.5 Hz, 1H) 8.01 (dd, J=8.0, 1.9 Hz, 1H) 8.14-8.19 (m, 2H) 8.57(d, J=2.7 Hz, 1H) 8.82-8.89 (m, 2H) 9.28 (s, 1H); MS (ESI(+)) m/e 453.3(M+H)⁺.

Example 356N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 352B and1-fluoro-4-isocyanato-2-trifluoromethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)d ppm 4.45 (s, 2H) 6.95 (d, J=7.5 Hz, 1H) 7.42-7.47 (m, 1H) 7.45 (d,J=8.5 Hz, 2H) 7.50 (d, J=7.5 Hz, 1H) 7.64 (d, J=8.5 Hz, 2H) 7.64-7.69(m, 1H) 7.71 (d, J=6.1 Hz, 2H) 8.03 (dd, J=6.6, 2.6 Hz, 1H) 8.68 (d,J=6.1 Hz, 2H) 8.99 (s, 1H) 9.11 (s, 1H) 11.98 (s, 1H); MS (ESI(+)) m/e507.2 (M+H)⁺.

Example 357N-[4-(3-amino-7-pyridin-4-yl-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 352B and1-fluoro-2-isocyanato-4-trifluoromethylbenzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H.Additionally, DMF was used in place of CH₂Cl₂. ¹H NMR (300 MHz, DMSO-D₆)d ppm 7.01 (d, J=7.5 Hz, 1H) 7.42-7.49 (m, 3H) 7.65-7.71 (m, 4H) 8.04(dd, J=6.4, 2.7 Hz, 1H) 8.14-8.21 (m, 2H) 8.82-8.90 (m, 2H) 9.12 (s, 1H)9.23 (s, 1H); MS (ESI(+)) m/e 507.7 (M+H)⁺.

Example 358N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)ureaExample 358A 5-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting2,5-difluoro-benzonitrile for example 243A in example 243B, thensubstituting the product for 2-fluoro-6-iodo-benzonitrile in example 1A.MS (ESI(+) m/e 278 (M+H)⁺.

Example 358BN-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea

The desired product was prepared by substituting1-bromo-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene and Example358B for 1A, respectively and in Examples 1B-C and purifying as inexample 3. ¹H NMR (300 MHz, DMSO-D₆) d ppm 7.15-7.38 (m, 7H) 7.61 (d,J=8.8 Hz, 2H) 7.88 (t, J=1.9 Hz, 1H) 8.95 (s, 1H) 8.95 (s, 1H) 11.82 (s,1H); MS (ESI(+)) m/e 439.9, 441.9 (M+H)⁺.

Example 359N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea

The desired product was prepared by substituting Example 358B for 1A inExamples 1C and purifying as in example 3. ¹H NMR (300 MHz, DMSO-D₆) dppm 2.29 (s, 3H) 4.19 (s, 2H) 6.80 (d, J=7.5 Hz, 1H) 7.14-7.30 (m, 4H)7.32 (s, 1H) 7.35 (d, J=8.5 Hz, 2H) 7.61 (d, J=8.5 Hz, 2H) 8.65 (s, 1H)8.83 (s, 1H) 11.74 (s, 1H); MS (ESI(+)) m/e 376.1 (M+H)⁺.

Example 360 N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting 1-isocyanatobenzene for1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively andin Examples 1B-C and purifying as in example 3. ¹H NMR (300 MHz,DMSO-D₆) d ppm 6.98 (t, J=7.3 Hz, 1H) 7.21 (t, J=9.3 Hz, 1H) 7.27-7.32(m, 3H) 7.36 (d, J=8.1 Hz, 2H) 7.48 (d, J=7.8 Hz, 2H) 7.61 (d, J=8.5 Hz,2H) 8.74 (s, 1H) 8.86 (s, 1H) 11.81 (s, 1H).

Example 361N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-fluoro-2-isocyanato-4-trifluoromethylbenzene for1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively andin Examples 1B-C. ¹H NMR (300 MHz, DMSO-D₆) d ppm 7.21 (t, J=9.2 Hz, 1H)7.29 (dd, J=9.2, 4.1 Hz, 1H) 7.37-3.40 (m, 4H) 7.63 (d, J=8.5 Hz, 2H)8.45-8.50 (m, 1H) 8.90 (d, J=2.4 Hz, 1H) 9.32 (s, 1H) 11.81 (br. s, 1H);MS (ESI(+)) m/e 448.1 (M+H)⁺.

Example 362N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 358B and 5A for1A and 1B, respectively in Examples 1C and purifying as in example 3. ¹HNMR (300 MHz, DMSO-D₆) d ppm 2.28 (s, 3H) 6.82 (ddd, J=8.5, 4.8, 2.0 Hz,1H) 7.12 (dd, J=11.5, 8.1 Hz, 1H) 7.25 (t, J=9.3 Hz, 1H) 7.33 (dd,J=9.2, 4.1 Hz, 1H) 7.38 (d, J=8.5 Hz, 2H) 7.62 (d, J=8.5 Hz, 2H) 8.01(dd, J=7.8, 2.0 Hz, 1H) 8.55 (d, J=2.4 Hz, 1H) 9.26 (s, 1H) 12.01 (br.s, 1H); MS (ESI(+)) m/e 394.0 (M+H)⁺.

Example 363N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-isocyanato-3-trifluoromethylbenzene for 1-isocyanato-3-methylbenzeneand Example 358B for 1A, respectively in Examples 1B-C and purifying asin example 3. ¹H NMR (300 MHz, DMSO-D₆) d ppm 7.22 (t, J=9.5 Hz, 1H)7.28-7.34 (m, 2H) 7.38 (d, J=8.1 Hz, 2H) 7.53 (t, J=8.0 Hz, 1H)7.59-7.65 (m, 3H) 8.04 (s, 1H) 9.01 (s, 1H) 9.14 (s, 1H) 11.85 (br. s,1H); MS (ESI(+)) m/e 430.0 (M+H)⁺.

Example 364N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting1-fluoro-4-isocyanato-3-trifluoromethylbenzene for1-isocyanato-3-methylbenzene and Example 358B for 1A, respectively inExamples 1B-C and purifying as in example 3. ¹H NMR (300 MHz, DMSO-D₆) dppm 7.23 (t, J=9.5 Hz, 1H) 7.32 (dd, J=9.2, 4.1 Hz, 1H) 7.38 (d, J=8.1Hz, 2H) 7.45 (t, J=9.5 Hz, 1H) 7.66 (m, 3H) 8.03 (dd, J=6.4, 2.7 Hz, 1H)9.04 (s, 1H) 9.15 (s, 1H) 11.94 (br. s, 1H); MS (ESI(+)) m/e 448.0(M+H)⁺.

Example 365N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea

The desired product was prepared by substituting1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene andExample 358B for 1A, respectively in Examples 1B-C and purifying as inexample 3. ¹H NMR (300 MHz, DMSO-D₆) d ppm 7.02-7.05 (m, 1H) 7.25 (t,J=9.5 Hz, 1H) 7.29-7.35 (m, 3H) 7.38 (d, J=8.5 Hz, 2H) 7.62 (d, J=8.5Hz, 2H) 7.73-7.75 (m, 1H) 9.00 (s, 1H) 9.01 (s, 1H) 12.01 (br. s, 1H);MS (ESI(+)) m/e 396.0 (M+H)⁺.

Example 366N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea

The desired product was prepared by substituting1-fluoro-4-isocyanato-3-methylbenzene for 1-isocyanato-3-methylbenzeneand Example 358B for 1A, respectively in Examples 1B-C and purifying asin example 3. ¹H NMR (300 MHz, DMSO-D₆) d ppm 2.22 (d, J=1.7 Hz, 3H)7.06 (t, J=9.2 Hz, 1H) 7.21-7.40 (m, 6H) 7.61 (d, J=8.5 Hz, 2H) 8.71 (s,1H) 8.88 (s, 1H) 12.01 (br. s, 1H); MS (ESI(+)) m/e 396.0 (M+H)⁺.

Example 367N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-chloro-4-fluorophenyl)urea

The desired product was prepared by substituting1-fluoro-2-chloro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzeneand Example 358B for 1A, respectively in Examples 1B-C and purifying asin example 3. ¹H NMR (300 MHz, DMSO-D₆) d ppm 7.24 (t, J=9.5 Hz, 1H)7.30-7.39 (m, 5H) 7.62 (d, J=8.8 Hz, 2H) 7.82-7.85 (m, 1H) 9.00 (s, 1H)9.01 (s, 1H) 11.99 (br. s, 1H); MS (ESI(+)) m/e 414.0 (M+H)⁺.

Example 368N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile and1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzenein Examples 1A-C. ¹H NMR (300 MHz, DMSO-D₆) d ppm 2.28 (s, 3H) 6.73 (d,J=7.5 Hz, 1H) 6.79-6.84 (m, 1H) 7.11 (dd, J=11.4, 8.3 Hz, 1H) 7.40 (d,J=8.8 Hz, 2H) 7.51 (d, J=7.80 Hz, 1H) 7.60 (d, J=8.8 Hz, 2H) 8.01 (dd,J=7.5, 2.0 Hz, 1H) 8.54 (d, J=2.4 Hz, 1H) 9.22 (s, 1H) 12.08 (br. s,1H); MS (ESI(+)) m/e 453.9, 455.9 (M+H)⁺.

Example 3693-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoicacid Example 369A 4-(4-aminophenyl)-1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-benzonitrilefor 15F in example 15G, then substituting the product for2-fluoro-6-benzonitrile in example 1A. MS (ESI(+)) m/e 225 (M+H)⁺.

Example 369B tert-butyl3-amino-4-(4-aminophenyl)-1H-indazole-1-carboxylate

A −78 C solution of 369A (100 mg, 0.45 mmol) in THF (6 mL) was treatedwith LDA (0.245 mL, 2M solution in heptane, 0.49 mmol), stirred at −50for 15 minutes, treated with solid (Boc)₂O (98 mg, 0.45 mmol). Thereaction was allowed to gradually warm up to room temperature over 2 h,concentrated in vacuo and purified via silica gel chromatography elutingfirst with 75% EtOAc: hexanes then with 8% methanol: CH₂Cl₂ to give 62mg of 369B. MS (ESI(+)) m/e 325 (M+H)⁺.

Example 369C methyl3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoate

A 0 C solution of 3-Amino-4-fluoro-benzoic acid methyl ester (29 mg,0.17 mmol) in THF (4 mL) was treated with triethyl amine (0.026 mL) and4-nitrophenyl chloroformate (38 mg), stirred at 0 C for 45 min, thentreated with a solution of example 396B (56 mg, 0.17 mmol) in THF (3 mL)followed by an additional 0.026 mL of Et3N. The resulting mixture wasallowed to warm up to room temperature slowly, stirred overnight,diluted with water and extracted twice with EtOAc. The combined organicswere washed with brine, dried (MgSO4), concentrated and purified viasilica gel chromatography eluting with EtOAc to give 98 mg of3-Amino-4-{4-[3-(2-fluoro-5-methoxycarbonyl-phenyl)-ureido]-phenyl}-indazole-1-carboxylicacid tert-butyl ester. This compound was dissolved in CH₂Cl₂ (2 mL),cooled to 0 C, treated with TFA (1 mL), stirred at 0 for 45 min then atroom temperature for 1 h. The reaction was quenched with sat. aq. NaHCO3adjusting the pH to 8-9 then extracted with EtOAc (3×). The combinedorganics were washed with brine, dried (MgSO4), concentrated andpurified via silica gel chromatography eluting with first EtOAc then 12%methanol:CH₂Cl₂ to give 30 mg of 369C as a white solid. MS (ESI(+)) m/e420 (M+H)⁺.

Example 369D3-[({[4-(3-amino-1H-indazol-4-yl)phenyl]amino}carbonyl)amino]-4-fluorobenzoicacid

A solution of 369C (20 mg, 0.05 mmol) in methanol (1 mL) was treatedwith a solution of NaOH 911 mg) in water (1 mL), stirred at reflux for 7h and concentrated. The residue was diluted with water, the pH wasadjusted to pH of 3 with 1 N HCl, and the resulting solid was collectedvia filtration to give 17 mg of 369D. H NMR (300 MHz, DMSO-D₆) d ppm4.34 (br. s, 2H) 6.79 (dd, J=5.3, 2.5 Hz, 1H) 7.24-7.28 (m, 2H)7.34-7.43 (m, 3H) 7.60-7.64 (m, 3H) 8.77 (d, J=2.7 Hz, 1H) 8.85 (dd,J=8.1, 2.0 Hz, 1H) 9.27 (s, 1H) 11.72 (br. s, 1H) 13.00 (br. s, 1H).

Example 370N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 182A for 1A inExample 5B. MS (ESI(+)Q1MS m/z 376 (M+H)⁺; ¹H NMR (300 MHz, DMSO-D₆) δppm 2.28 (s, 3H) 6.78-6.84 (m, 1H) 7.11 (dd, J=11.36, 8.31 Hz, 1H) 7.33(dd, J=8.65, 1.19 Hz, 1H) 7.48 (s, 1H) 7.57 (d, J=8.82 Hz, 2H) 7.67 (d,J=8.82 Hz, 2H) 7.84 (d, J=8.48 Hz, 1H) 8.00 (dd, J=7.80, 2.37 Hz, 1H)8.51 (d, J=2.71 Hz, 1H) 9.19 (s, 1H)

Example 371N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide

The desired product was prepared by substituting Example 178A forExample 15G in Example 15H. MS (ESI(+)Q1MS m/z 499 (M+H)⁺; ¹H NMR (500MHz, DMSO-D₆) δ ppm 2.99 (s, 3H) 3.44 (q, J=5.61 Hz, 2H) 4.23 (t, J=5.61Hz, 2H) 6.72 (d, J=7.49 Hz, 1H) 6.79 (td, J=8.58, 2.18 Hz, 1H) 6.83 (d,J=7.80 Hz, 1H) 7.13-7.17 (m, 2H) 7.29-7.34 (m, 1H) 7.37 (d, J=8.42 Hz,2H) 7.51 (dt, J=11.93, 2.30 Hz, 1H) 7.57 (d, J=8.73 Hz, 2H) 8.85 (s, 1H)8.94 (s, 1H)

Example 372N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 248B and1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for Example 15G and1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS(ESI(+)Q1MS m/z 531 (M+H)⁺; ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.15-2.20(m, 2H) 2.86 (d, J=5.09 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J=5.76 Hz,2H) 6.72 (d, J=7.46 Hz, 1H) 6.81 (d, J=7.80 Hz, 1H) 7.36 (d, J=8.48 Hz,2H) 7.45 (t, J=9.83 Hz, 1H) 7.58 (d, J=8.48 Hz, 2H) 7.63-7.69 (m, 1H)8.04 (dd, J=6.44, 2.71 Hz, 1H) 9.02 (s, 1H) 9.18 (s, 1H)

Example 373N-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 373A 1-acetyl-4-iodo-1H-indazol-3-amine

A solution of example 1A (215 mg, 0.83 mmol), acetic anhydride (0.086mL) and 18-crown-6 (438 mg) in CH₂Cl₂ (5 mL) was stirred at roomtemperature overnight, then partitioned between EtOAc and water. Theorganic extract was dried (MgSO4), concentrated and purified via silicagel chromatography eluting with 1 to 1 hexane:EtOAc to give 110 mg of373A. ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.53 (s, 3H) 6.01 (s, 2H) 7.26 (t,J=7.46 Hz, 1H) 7.77 (d, J=7.46 Hz, 1H) 8.31 (d, J=8.48 Hz, 1H).

Example 373BN-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 373A for 1A inExample 5B. MS (ESI(−)Q1MS m/z 416 (M−H)⁻; ¹H NMR (300 MHz, DMSO-D₆) δppm 2.28 (s, 3H) 2.55 (s, 3H) 5.20 (s, 2H) 6.79-6.84 (m, 1H) 7.12 (dd,J=11.53, 8.48 Hz, 1H) 7.18 (d, J=7.46 Hz, 1H) 7.42 (d, J=8.48 Hz, 2H)7.57-7.64 (m, 3H) 8.00 (dd, J=7.63, 1.87 Hz, 1H) 8.29 (d, J=8.14 Hz, 1H)8.56 (d, J=2.71 Hz, 1H) 9.26 (s, 1H)

Example 374N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(4-bromo-3-methylphenyl)urea

The desired product was prepared as the trifluoroacetate salt bysubstituting Example 26B and 1-bromo-4-isocyanato-2-methylbenzene forExample 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example15H. MS (ESI (+)): m/e 456 (M+H); ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.32(s, 3H) 6.74 (dd, J=7.80, 4.41 Hz, 1H) 7.13 (dd, J=11.19, 7.80 Hz, 1H)7.27 (dd, J=8.65, 2.54 Hz, 1H) 7.37 (d, J=8.48 Hz, 2H) 7.44-7.49 (m, 2H)7.58 (d, J=8.48 Hz, 2H) 8.80 (s, 1H) 8.87 (s, 1H).

Example 375N-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaExample 375A2-(4-iodo-1-phenyl-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione

A mixture of 162A (940 mg), phenyl boronic acid (590 mg), cupric acetate(440 mg), triethylamine (0.674 mL) in CH₂Cl₂ (20 mL) was stirred at roomtemperature overnight, then concentrated. The residue was purified viasilica gel chromatography eluting with 20% EtOAc in hexane to give 770mg of 375A. MS (ESI(+)) m/e 466.1 (M+H)⁺.

Example 375B 4-iodo-1-phenyl-1H-indazol-3-amine

The desired product was prepared by substituting 375A for 162B inexample 162C. MS (ESI(+)) m/e 336.1 (M+H)⁺.

Example 375CN-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 375B for 1A inExample 5B. MS (ESI(+)Q1MS m/z 452 (M+H)⁺; ¹H NMR (300 MHz, DMSO-D₆) δppm 2.29 (s, 3H) 4.75 (s, 2H) 6.83 (m, 1H) 6.97 (d, J=6.44 Hz, 1H) 7.12(dd, J=11.53, 8.48 Hz, 1H) 7.26 (t, J=7.29 Hz, 1H) 7.43-7.47 (m, 3H)7.50-7.55 (m, 2H) 7.61-7.74 (m, 5H) 8.01 (dd, J=7.97, 2.20 Hz, 1H) 8.57(d, J=2.37 Hz, 1H) 9.26 (s, 1H)

Example 376N-{4-[3-amino-7-(3-pyridin-3-ylpropoxy)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The desired product was prepared by substituting Example 338B and1-fluoro-2-isocyanato-4-methylbenzene for Example 1A and1-isocyanato-3-methylbenzene, respectively, in Examples 1B-C. MS(ESI(+)Q1MS m/z 511 (M+H); ¹H NMR (300 MHz, DMSO-D₆) δ ppm 2.14-2.18 (m,2H) 2.28 (s, 3H) 3.01 (t, J=7.4 Hz, 2H) 4.14 (t, J=6.10 Hz, 2H) 6.70 (d,J=7.80 Hz, 1H) 6.77-6.84 (m, 2H) 7.11 (dd, J=11.36, 8.31 Hz, 1H) 7.37(d, J=8.82 Hz, 2H) 7.56 (d, J=8.48 Hz, 2H) 7.70-7.73 (m, 1H) 8.01 (dd,J=7.97, 2.20 Hz, 1H) 8.17 (d, J=9.49 Hz, 1H) 8.52 (d, J=3.05 Hz, 1H)8.62 (d, J=5.09 Hz, 1H) 8.70 (s, 1H) 9.17 (s, 1H).

Example 377 N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N′-phenylurea

The desired product was prepared by substituting Example 182A andN-phenyl)N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 1A and 5A respectively, in Example 5B. MS (ESI(+)Q1MS m/z 344(M+H)⁺; ¹H NMR (300 MHz, DMSO-D₆) δ ppm 5.33 (s, 2H) 6.97 (t, J=7.29 Hz,1H) 7.19 (dd, J=8.31, 1.19 Hz, 1H) 7.28 (t, J=7.97 Hz, 2H) 7.38 (s, 1H)7.48 (d, J=7.46 Hz, 2H) 7.59 (m, 4H) 7.72 (d, J=8.48 Hz, 1H) 8.90 (s,1H) 8.96 (s, 1H) 11.38 (s, 1H)

Example 378N-[4-(3-amino-1H-indazol-6-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The desired product was prepared by substituting Example 182A andN-(3-trifluoromethylphenyl)-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor 1A and 5A respectively, in Example 5B. MS (ESI(+)Q1MS m/z 412(M+H)⁺; ¹H NMR (300 MHz, DMSO-D₆) δ ppm 7.33 (dd, J=7.97, 4.58 Hz, 2H)7.55-7.58 (m, 3H) 7.58 (d, J=8.82 Hz, 2H) 7.67 (d, J=8.82 Hz, 2H) 7.85(d, J=8.48 Hz, 1H) 8.04 (s, 1H) 8.95 (s, 1H) 9.11 (s, 1H).

Example 379 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-thien-3-ylurea

The desired product was prepared by substituting 3-isocyanato-thiophenefor 1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 4.33 (s, 2H) 6.78 (dd, J=5.59, 2.20 Hz, 1H) 7.07 (dd,J=5.09, 1.36 Hz, 1H) 7.24-7.28 (m, 2H) 7.29-7.33 (m, 1H) 7.39 (d, J=8.48Hz, 2H) 7.45 (dd, J=5.09, 3.39 Hz, 1H) 7.59 (d, J=8.48 Hz, 2H) 8.78 (s,1H) 8.99 (s, 1H) 11.70 (s, 1H); MS (ESI (+)) m/e 350 (M+H)⁺.

Example 380 N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-cyclopentylurea

The desired product was prepared by substituting isocyanato-cyclopentanefor 1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz,DMSO-D₆) δ ppm 1.31-1.45 (m, 2H) 1.47-1.71 (m, 4H) 1.77-1.93 (m, 2H)3.89-4.00 (m, 1H) 4.31 (s, 2H) 6.21 (d, J=7.12 Hz, 1H) 6.75 (dd, J=5.59,2.20 Hz, 1H) 7.22-7.27 (m, 2H) 7.32 (d, J=8.48 Hz, 2H) 7.50 (d, J=8.48Hz, 2H) 8.39 (s, 1H) 11.68 (s, 1H). MS (ESI (+)) m/e 336 (M+H)⁺.

It will be evident to one skilled in the art that the present inventionis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A compound of formula (I)

or a therapeutically acceptable salt thereof, wherein A is phenyl; X isNR⁹; R¹ and R² are independently selected from the group consisting ofhydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl,aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy,hydroxyalkoxy, hydroxyalkyl, (NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkenyl,(NR^(a)R^(b))alkyl, (NR^(a)R^(b))alkynyl, (NR^(a)R^(b))carbonylalkenyl,and (NR^(a)R^(b))carbonylalkyl; R³ and R⁴ are each independentlyselected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy,alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; R⁵ is LR⁶; L isselected from the group consisting of (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n)and CH₂C(O)NR⁷, wherein m is 0 and n is 0, and wherein each group isdrawn with its left end attached to A; R⁶ is selected from the groupconsisting of hydrogen, aryl, cycloalkyl, heterocyclyl, and1,3-benzodioxolyl wherein the 1,3-benzodioxolyl can be optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of alkenyl, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl,aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, asecond heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl,nitro, —NR^(c)R^(d), and (NR^(c)R^(d))alkyl; R⁷ and R⁸ are independentlyselected from the group consisting of hydrogen and alkyl; R⁹ is selectedfrom the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl,alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and(NR^(a)R^(b))alkyl; R^(a) and R^(b) are independently selected from thegroup consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl,haloalkylsulfonyl, and cycloalkyl; and R^(c) and R^(d) are independentlyselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyalkyl andheterocyclyl.
 2. The compound of claim 1 of formula (II)

or a therapeutically acceptable salt thereof, wherein R¹ and R² areindependently selected from the group consisting of hydrogen, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl,(NR^(a)R^(b))alkoxy, (NR^(a)R^(b))alkenyl, (NR^(a)R^(b))alkyl,(NR^(a)R^(b))carbonylalkenyl, and (NR^(a)R^(b))carbonylalkyl; R³ and R⁴are independently selected from the group consisting of hydrogen,alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy; L is selectedfrom the group consisting of (CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n) andCH₂C(O)NR⁷, wherein m is 0 and n is 0 , and wherein each group is drawnwith its left end attached to the ring substituted with R³ and R⁴; R⁷and R⁸ are independently selected from the group consisting of hydrogenand alkyl; R⁹ is selected from the group consisting of hydrogen,alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,hydroxyalkyl, and (NR^(a)R^(b))alkyl; R¹⁰ and R¹¹ are independentlyselected from the group consisting of hydrogen, alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo,haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and —NR^(c)R^(d);R^(a) and R^(b) are independently selected from the group consisting ofhydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, andhaloalkylsulfonyl; and R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.
 3. Thecompound of claim 2 wherein L is CH₂C(O)NR⁷.
 4. The compound of claim 3selected from the group consisting of2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-chlorophenyl)acetamide;2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide;2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-[3-(trifluoromethyl)phenyl]acetamide;2-[4-(3-amino-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide; and2-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N-(3-methylphenyl)acetamide.5. The compound of claim 2 wherein L is(CH₂)_(m)N(R⁷)C(O)N(R⁸)(CH₂)_(n).
 6. The compound of claim 5 wherein R⁷and R⁸ are hydrogen, and R⁹ is selected from the group consisting ofalkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl,hydroxyalkyl, and (NR^(a)R^(b))alkyl.
 7. The compound of claim 6selected from the group consisting ofN-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-phenyl urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(2-methylphenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(4-methylphenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methoxyphenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-{4-[3-amino-1-(2-hydroxyethyl)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea;N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea;N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-1-[2-(4-morpholinyl)ethyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1-methyl-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-1-[2-(dimethylamino)ethyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-{4-[3-amino-1-(2-methoxyethyl)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(1-acetyl-3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea;andN-[4-(3-amino-1-phenyl-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea.8. The compound of claim 5 wherein R⁷ and R⁸ are hydrogen, and R⁹ ishydrogen.
 9. The compound of claim 8 selected from the group consistingofN-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-7-[(dimethylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-7-hydroxy-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea;N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea;N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(3-chlorophenyl)urea;N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(3-methylphenyl)urea;N-{4-[3-amino-7-fluoro-6-(hydroxymethyl)-1H-indazol-4-yl]phenyl}-N′-(3-fluorophenyl)urea;N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-6-[(diethylamino)methyl]-7-fluoro-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea;N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea;andN-(4-{3-amino-7-[(isopropylamino)methyl]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylphenyl)urea.10. The compound of claim 8 selected from the group consisting ofN-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-6-bromo-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(4-fluorophenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(2-fluorophenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-7-fluoro-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-phenylurea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea;N-[4-(3-amino-5-fluoro-1H-indazol-4-yl)phenyl]-N′-(3-chloro-4-fluorophenyl)urea;N-[4-(3-amino-7-bromo-1H-indazol-4-yl)phenyl]-N′-(2-fluoro-5-methylphenyl)urea;andN-[4-(3-amino-7-fluoro-1H-indazol-4-yl)phenyl]-N′-(4-bromo-3-methylphenyl)urea.11. The compound of claim 1 wherein one of R¹ and R² is hydrogen and theother is selected from the group consisting of(NR^(a)R^(b))carbonylalkenyl and (NR^(a)R^(b))alkoxy.
 12. The compoundof claim 11 selected from the group consisting ofN-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylurea;N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-3-bromophenyl)urea;N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea;N-(4-{3-amino-7-[2-(dimethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-phenylurea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-bromophenyl)urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-7-[2-(diethylamino)ethoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide;N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide;N-{2-[(3-amino-4-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide;N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide;N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}methanesulfonamide,N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide;N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide;N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]-1,1,1-trifluoromethanesulfonamide;N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide;N-{2-[(3-amino-4-{4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-1H-indazol-7-yl)oxy]ethyl}benzenesulfonamide;N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide;N-[2-({3-amino-4-[4-({[(3-chlorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]benzenesulfonamide;N-[2-({3-amino-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide;N-[2-({3-amino-4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]thiophene-2-sulfonamide;N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-{4-(3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-(4-{3-amino-7-[3-(diethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea;N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyl)urea;N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylphenyl)urea;N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-fluorophenyl)urea;N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(3-chlorophenyl)urea;N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylphenyl)urea;N-[2-({3-amino-4-[4-({[(3-fluorophenyl)amino]carbonyl}amino)phenyl]-1H-indazol-7-yl}oxy)ethyl]methanesulfonamide;andN-(4-{3-amino-7-[3-(dimethylamino)propoxy]-1H-indazol-4-yl}phenyl)-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea.13. The compound of claim 1 wherein one of R¹ and R² is hydrogen and theother is selected from the group consisting of alkoxy, alkoxyalkoxy, andalkyl.
 14. The compound of claim 1 wherein one of R³ and R⁴ is hydrogenand the other is selected from the group consisting of alkoxyalkoxy,alkyl, halo, haloalkoxy, and hydroxy.
 15. The compound of claim 14selected from the group consisting ofN-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-fluorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3,5-dimethylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-ethylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chloro-4-fluorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-fluoro-4-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-methylphenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-ethylphenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(3-chlorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-3-fluorophenyl]-N′-(4-fluoro-3-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-hydroxyphenyl]-N′-(2-fluoro-5-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)-2-(trifluoromethoxy)phenyl]-N′-(2-fluoro-5-methylphenyl)ureaandN-[4-(3-amino-1H-indazol-4-yl)-2-fluorophenyl]-N′-(2-fluoro-5-methylphenyl)urea.16. The compound of claim 1 wherein R³ and R⁴ are hydrogen.
 17. Thecompound of claim 16 selected from the group consisting ofN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-3,5-dimethoxyphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-bromophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-bromo-4-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-ethylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-phenylurea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-fluoro-4-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(2-fluorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(4-fluorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-fluorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-hydroxyphenyl)urea;N-[3-(3-amino-1H-indazol-4-yl)phenyl]-N′-(3-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(4-bromo-2-fluorophenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(5-fluoro-2-methylphenyl)urea;N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-(4-fluoro-3-methylphenyl)urea;andN-[4-(3-amino-1H-indazol-4-yl)phenyl]-N′-[2-fluoro-5-(hydroxymethyl)phenyl]urea.18. The compound of claim 2 wherein R¹ and R² are independently selectedfrom the group consisting of hydrogen, alkoxy, alkoxyalkoxy,alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl,hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR^(a)R^(b))alkoxy,(NR^(a)R^(b))alkenyl, (NR^(a)R^(b))alkyl, (NR^(a)R^(b))carbonylalkenyl,and (NR^(a)R^(b))carbonylalkyl.
 19. A pharmaceutical compositioncomprising a compound of claim 1 or a therapeutically acceptable saltthereof, in combination with a therapeutically acceptable carrier. 20.The compound of claim 8 wherein one of R¹ and R² is hydrogen and theother is aryloxyalkyl.
 21. The compound of claim 1 selected from thegroup consisting ofN-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(2-fluoro-5-methylpheny)urea;N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-chloropheny)urea;N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazo1-4-yl}phenyl)-N′-[3-(trifluoromethyl)phenyl]urea;N-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(3-methylphenyOurea;andN-(4-{3-amino-7-[(4-chlorophenoxy)methyl]-1H-indazol-4-yl}phenyl)-N′-(4-fluoro-3-methylpheny)urea.